Substituted benzimidazoles and their use for inducing apoptosis

ABSTRACT

The invention relates to compounds of formula (I) 
                         
wherein R represents aryl or heteroaryl, X is a bond, a carbonyl group, a derivative of a carbonyl group, an ethylene group or an ethylenecarbonyl group, R 1  is optionally substituted amino or hydroxy, and the substituents R 2  to R 6  have the meanings given in the specification, to methods of synthesis of such compounds, to pharmaceutical compositions containing compounds of formula (I), to intermediates, to the use of a compounds of formula (I) as a medicament and for the preparation of a pharmaceutical composition for the treatment of neoplastic and autoimmune diseases, and to methods of treatment of neoplastic and autoimmune diseases using such compounds of formula (I) or of pharmaceutical compositions containing same.

CROSS-REFERENCE TO RELATED APPLICATION

This Application is a Divisional Application of application Ser. No.11/501,648 filed Aug. 9, 2006, now U.S. Pat. No. 7,423,157 which is aCIP of U.S. Ser. No. 10/587,675 filed Jul. 27, 2006 now abandoned whichwas filed as a 35 U.S.C. 371 National Application with respect toPCT/EP2005/050586 filed on Feb. 10, 2005 which claims as priorityEuropean Patent Application No. 04405082.1 filed on Feb. 11, 2004.

FIELD OF THE INVENTION

The invention relates to novel substituted benzimidazoles, processes forthe preparation thereof, pharmaceutical compositions containing same,the use thereof optionally in combination with one or more otherpharmaceutically active compounds for the therapy of neoplastic diseasesand autoimmune diseases, and a method for the treatment of such adiseases.

BACKGROUND OF THE INVENTION

Cancer is one of the leading causes of death in humans. Although avariety of drugs against neoplastic diseases have been developed andtechniques are available such as surgery and radiation therapy, there isstill a need for alternative and improved methods of treatment ofneoplastic diseases.

Autoimmune diseases are associated with abnormal lymphoproliferation asa result of defects in the termination of lymphocyte activation andgrowth. Often, such diseases are associated with inflammation likerheumatoid arthritis, insulin dependent diabetes mellitus, multiplesclerosis, systemic lupus erythematosus and the like. The treatment ofsuch diseases is focused on anti-inflammatory and immunosuppressivedrugs which in numerous cases show severe side effects. Hence, there isa need for alternative drugs with a new mode of action showing less sideeffects.

Apoptosis is a term used to describe a series of cellular events whichoccur to bring about programmed cell death. There are various apoptoticpathways, some of which have been characterized, whereas others remainto be elucidated. If the balance between cell division and apoptosis isdisturbed, life-threatening diseases including cancer, autoimmunedisorders, neurodegenerative and cardiovascular diseases may occur.

In recent years it has become evident that programmed cell death(apoptosis) is as important to the health of a multicellular organism ascell division. By repeated cell division and differentiation throughoutdevelopment or tissue repair, surplus or even harmful cells aregenerated. In order to maintain tissue homeostasis these cells have tobe removed or killed. The delicate interplay between cell growth andapoptosis in an organism is mirrored in the complex molecular balancethat determines whether an individual cell undergoes division, arrestsin the cell cycle or commits to programmed cell death.

Dysregulation of cell proliferation, or lack of appropriate cell death,has wide ranging clinical implications. A number of diseases associatedwith such dysregulation involve hyperproliferation, inflammation, tissueremodeling and repair. Familiar indications in this category includecancers, restenosis, neointimal hyperplasia, angiogenesis,endometriosis, lymphoproliferative disorders, transplantation relatedpathologies (graft rejection), polyposis, loss of neural function in thecase of tissue remodeling and the like. Such cells may lose the normalregulatory control of cell division, and may also fail to undergoappropriate cell death.

As apoptosis is inhibited or delayed in most types of proliferative,neoplastic diseases, induction of apoptosis is an option for treatmentof cancer, especially in cancer types which show resistance to classicchemotherapy, radiation and immunotherapy (Apoptosis and CancerChemotherapy, Hickman and Dive, eds., Blackwell Publishing, 1999). Alsoin autoimmune and transplantation related diseases and pathologiescompounds inducing apoptosis may be used to restore normal cell deathprocesses and therefore can eradicate the symptoms and might cure thediseases. Further applications of compounds inducing apoptosis may be inrestenosis, i.e. accumulation of vascular smooth muscle cells in thewalls of arteries, and in persistent infections caused by a failure toeradicate bacteria- and virus-infected cells. Furthermore, apoptosis canbe induced or re-established in epithelial cells, in endothelial cells,in muscle cells, and in others which have lost contact withextracellular matrix. These cells are potentially able to colonize otherorgans and therefore can develop into pathologies like neoplasias,endometriosis and the like.

SUMMARY OF THE INVENTION

Triazolo- and pyrazolo-benzimidazoles of formula (I) are selectivelyinducing apoptosis in cancer cells, and can be used for the treatment ofneoplastic and autoimmune diseases. The invention relates to compoundsof formula (I), to methods of synthesis of such compounds, topharmaceutical compositions containing compounds of formula (I), to theuse of a compound of formula (I) as a medicament and for the preparationof a pharmaceutical composition for the treatment of neoplastic andautoimmune diseases, and to methods of treatment of neoplastic andautoimmune diseases using such compounds of formula (I) or ofpharmaceutical compositions containing same.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to compounds of formula (I)

wherein

-   R represents aryl or heteroaryl optionally substituted by up to four    substituents independently selected from-   alkyl, cycloalkyl, cycloalkyl-lower alkyl, halo-lower alkyl,    hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-lower    alkoxy-lower alkyl, halo-lower alkoxy-lower alkyl, acyloxy-lower    alkyl, heterocyclyl, heterocyclyl-lower alkyl, optionally    substituted phenyl, optionally substituted phenyl-lower alkyl,    optionally substituted heteroaryl, optionally substituted    heteroaryl-lower alkyl, optionally substituted alkenyl, optionally    substituted alkinyl,-   hydroxy, lower alkoxy, optionally substituted alkenyloxy, optionally    substituted alkinyloxy, cycloalkoxy, halo-lower alkoxy,    cycloalkyl-lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower    alkoxy, heterocyclyloxy, heterocyclyl-lower alkoxy, optionally    substituted phenyloxy, optionally substituted phenyl-lower alkoxy,    optionally substituted heteroaryloxy, optionally substituted    heteroaryl-lower alkoxy, sulfamoyloxy, carbamoyloxy, lower    alkylcarbonyloxy,-   amino, monoalkylamino, dialkylamino, aminocarbonylamino wherein each    of the two amino groups is optionally substituted by alkyl, alkenyl,    alkinyl or alkoxy-lower alkyl, heterocyclylcarbonylamino wherein    heterocyclyl is bound via a nitrogen atom, aminosulfonylamino    wherein each of the two amino groups is optionally substituted by    alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,    heterocyclylsulfonylamino wherein heterocyclyl is bound via a    nitrogen atom, lower alkoxycarbonylamino, lower alkylcarbonylamino    wherein alkyl is optionally substituted by one or two substituents    selected from optionally substituted phenyl, guanidyl, halogen,    cyano, alkoxy, optionally substituted phenoxy, alkylmercapto and    optionally substituted amino; lower alkenylcarbonylamino wherein    alkenyl is optionally substituted by one or two substituents    selected from lower alkyl, halo-lower alkyl, optionally substituted    phenyl, halogen, cyano, alkoxy and optionally substituted amino;    amino-lower alkyl or amino-lower alkylamino, wherein the nitrogen    atom is unsubstituted or substituted by one or two substitutents    selected from lower alkyl, cycloalkyl, cycloalkyl-lower alkyl,    hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally    substituted phenyl, optionally substituted phenyl-lower alkyl,    optionally substituted heteroaryl, optionally substituted    heteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the two    substituents on nitrogen form together with the nitrogen    heterocyclyl,-   lower alkylcarbonyl, cycloalkylcarbonyl, optionally substituted    phenylcarbonyl, optionally substituted heteroarylcarbonyl,    heterocyclylcarbonyl,-   carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower    alkoxy-lower alkoxycarbonyl, optionally substituted phenyl-lower    alkoxycarbonyl, cyano,-   lower alkylmercapto, optionally substituted phenylmercapto, lower    alkylsulfinyl, halo-lower alkylsulfinyl, optionally substituted    phenylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl,    optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, and    nitro;-   and wherein two adjacent substituents together with the atoms of    aryl or heteroaryl may form a 5 or 6 membered carbocyclic or    heterocyclic ring;-   X represents a bond; oxygen; a group C═Y, wherein Y stands for    oxygen, nitrogen substituted by hydroxy, alkoxy or optionally    substituted amino; a group —CH═CH—(C═O)_(n)— or —(C═O)_(n)—CH═CH—    wherein n is 0 or 1; or a group CR⁷R⁸;-   Q represents N or CR⁹;-   R¹ represents a group NR¹⁰R¹¹ or OR¹²;-   R² represents hydrogen, lower alkyl or amino;-   R³, R⁴, R⁵ and R⁶, independently of each other, represent hydrogen,    lower alkyl, halo-lower alkyl, cyano-lower alkyl, carboxy-lower    alkyl, cycloalkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl,    lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl,    halo-lower alkoxy-lower alkyl, heterocyclyl, heterocyclyl-lower    alkyl, optionally substituted phenyl, optionally substituted    phenyl-lower alkyl, optionally substituted heteroaryl, optionally    substituted heteroaryl-lower alkyl, optionally substituted alkenyl,    optionally substituted alkinyl,-   hydroxy, lower alkoxy, halo-lower alkoxy, cycloalkoxy,    cycloalkyl-lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower    alkoxy, heterocyclyloxy, heterocyclyl-lower alkoxy, optionally    substituted phenyloxy, optionally substituted phenyl-lower alkoxy,    optionally substituted heteroaryloxy, optionally substituted    heteroaryl-lower alkoxy, amino, carbamoyl, sulfamoyl, amino-lower    alkyl or amino-lower alkylamino, wherein in each case the nitrogen    atom is unsubstituted or substituted by one or two substitutents    selected from lower alkyl, cycloalkyl, cycloalkyl-lower alkyl,    hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally    substituted phenyl, optionally substituted phenyl-lower alkyl,    optionally substituted heteroaryl, optionally substituted    heteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the two    substituents on nitrogen form together with the nitrogen    heterocyclyl,-   lower alkylcarbonyl, cycloalkylcarbonyl, optionally substituted    phenylcarbonyl, optionally substituted heteroarylcarbonyl,    heterocyclylcarbonyl,-   carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower    alkoxy-lower alkoxycarbonyl, optionally substituted phenyl-lower    alkoxycarbonyl, cyano,-   lower alkylmercapto, optionally substituted phenylmercapto, lower    alkylsulfinyl, halo-lower alkylsulfinyl, optionally substituted    phenylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl,    optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, or    nitro,-   or R³ and R⁴, R⁴ and R⁵, or R⁵ and R⁶ together with the atoms of the    phenyl ring form a 5 or 6 membered carbocyclic or heterocyclic ring;-   R⁷ represents hydrogen, lower alkyl, cycloalkyl, cycloalkyl-lower    alkyl, lower alkenyl, lower alkinyl, optionally substituted phenyl,    lower alkoxy, lower alkenyloxy, lower alkinyloxy;-   R⁸ represents hydrogen, lower alkyl, hydroxy, lower alkoxy or lower    alkenyloxy, or R⁷ and R⁸ together with the carbon they are bound to    form a 5 or 6 membered carbocyclic or heterocyclic ring;-   R⁹ represents hydrogen, lower alkyl or amino;-   R¹⁰ and R¹¹, independently of each other, represent hydrogen, alkyl,    cycloalkyl, cycloalkyl-alkyl, optionally substituted arylalkyl,    optionally substituted heteroarylalkyl, hydroxyalkyl, alkoxyalkyl,    hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, cyanoalkyl, carboxyalkyl,    optionally substituted alkenyl, optionally substituted alkinyl, or    lower alkylcarbonyl wherein lower alkyl is optionally substituted by    one or two substitutents selected from aryl, optionally substituted    amino, alkoxy and aryloxy;-   or R¹⁰ and R¹¹ together with the atom they are bound to form    heterocyclyl;-   R¹² is hydrogen, lower alkyl, acyl or aminocarbonyl wherein amino is    unsubstituted or substituted by lower alkyl;-   tautomers and salts thereof.

The general terms used hereinbefore and hereinafter preferably havewithin the context of this disclosure the following meanings, unlessotherwise indicated:

The prefix “lower” denotes a radical having up to and including amaximum of 7, especially up to and including a maximum of 4 carbonatoms, the radicals in question being either linear or branched withsingle or multiple branching.

Where the plural form is used for compounds, salts, and the like, thisis taken to mean also a single compound, salt, or the like.

Double bonds in principle can have E- or Z-configuration. The compoundsof this invention may therefore exist as isomeric mixtures or singleisomers. If not specified both isomeric forms are intended.

Any asymmetric carbon atoms may be present in the (R)-, (S)- or(R,S)-configuration, preferably in the (R)- or (S)-configuration. Thecompounds may thus be present as mixtures of isomers or as pure isomers,preferably as enantiomer-pure diastereomers.

The invention relates also to possible tautomers of the compounds offormula (I).

Alkyl has from 1 to 12, preferably from 1 to 7 carbon atoms, and islinear or branched. Alkyl is preferably lower alkyl.

Lower alkyl has 1 to 4 carbon atoms and is butyl, such as n-butyl,sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl,ethyl or methyl. Preferably lower alkyl is methyl or ethyl.

Cycloalkyl has preferably 3 to 7 ring carbon atoms, and may beunsubstituted or substituted, e.g. by lower alkyl or lower alkoxy.Cycloalkyl is, for example, cyclohexyl, cyclopentyl, ormethylcyclopentyl.

Aryl stands for a mono- or bicyclic fused ring aromatic group with 5 to10 carbon atoms, such as phenyl, 1-naphthyl or 2-naphthyl, or also apartially saturated bicyclic fused ring comprising a phenyl group, suchas indanyl, dihydro- or tetrahydronaphthyl.

In optionally substituted phenyl, substituents are preferably loweralkyl, lower alkoxy, lower alkoxy-lower alkoxy, methylenedioxy,halo-lower alkyl, lower alkoxy-lower alkyl, halo, or nitro.

Heteroaryl represents an aromatic group containing at least oneheteroatom selected from nitrogen, oxygen and sulfur, and is mono- orbicyclic. Monocyclic heteroaryl includes 5 or 6 membered heteroarylgroups containing 1, 2, 3 or 4 heteroatoms selected from nitrogen,sulfur and oxygen. Bicyclic heteroaryl includes 9 or 10 memberedfused-ring heteroaryl groups. Examples of heteroaryl include pyrrolyl,thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, benzo fused derivatives of suchmonocyclic heteroaryl groups, such as indolyl, benzimidazolyl orbenzofuryl, quinolinyl, isoquinolinyl, quinazolinyl, or purinyl.

In optionally substituted heteroaryl, substituents are preferably loweralkyl, lower alkoxy, lower alkoxy-lower alkoxy, amino, optionallysubstituted by one or two substituents selected from lower alkyl, loweralkenyl and alkylcarbonyl, halo-lower alkyl, lower alkoxy-lower alkyl,halo, or nitro.

Alkenyl contains one or more, e.g. two or three, double bonds, and ispreferably lower alkenyl, such as 1- or 2-butenyl, 1-propenyl, allyl orvinyl.

Alkinyl is preferably lower alkinyl, such as propargyl or acetylenyl.

Ethylenediyl designates a vinyl group bound to R and to methylene asdefined in formula (I). The bonds to R and to methylene may be ingeminal or vicinal position of the vinyl group.

In optionally substituted alkenyl or alkinyl, substituents arepreferably lower alkyl, lower alkoxy, halo or di(lower alkyl)amino, andare connected with a saturated carbon atom of alkenyl or alkinyl or withan unsaturated carbon atom of alkenyl.

Heterocyclyl designates preferably a saturated, partially saturated orunsaturated, mono- or bicyclic ring containing 4-10 atoms comprisingone, two or three heteroatoms selected from nitrogen, oxygen and sulfur,which may, unless otherwise specified, be carbon or nitrogen linked,wherein a ring nitrogen atom may optionally be substituted by a groupselected from lower alkyl, amino-lower alkyl, aryl, aryl-lower alkyl andacyl, and a ring carbon atom may be substituted by lower alkyl,amino-lower alkyl, aryl, aryl-lower alkyl, heteroaryl, lower alkoxy,hydroxy or oxo. Examples of heterocyclyl are pyrrolidinyl, oxazolidinyl,thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, dioxolanyl andtetrahydropyranyl.

Acyl designates, for example, alkylcarbonyl, cyclohexylcarbonyl,arylcarbonyl, aryl-lower alkylcarbonyl, or heteroarylcarbonyl. Loweracyl is preferably lower alkylcarbonyl, in particular propionyl oracetyl.

Hydroxyalkyl is especially hydroxy-lower alkyl, preferablyhydroxymethyl, 2-hydroxyethyl or 2-hydroxy-2-propyl.

Cyanoalkyl designates preferably cyanomethyl and cyanoethyl.

Haloalkyl is preferably fluoroalkyl, especially trifluoromethyl,3,3,3-trifluoroethyl or pentafluoroethyl.

Halogen is fluorine, chlorine, bromine, or iodine.

Lower alkoxy is especially methoxy, ethoxy, isopropyloxy, ortert-butyloxy.

Arylalkyl includes aryl and alkyl as defined hereinbefore, and is e.g.benzyl, 1-phenethyl or 2-phenethyl.

Heteroarylalkyl includes heteroaryl and alkyl as defined hereinbefore,and is e.g. 2-, 3- or 4-pyridylmethyl, 1- or 2-pyrrolylmethyl,1-pyrazolylmethyl, 1-imidazolylmethyl, 2-(1-imidazolyl)ethyl or3-(1-imidazolyl)propyl.

Two adjacent substituents which together with the atoms of aryl orheteroaryl may form a 5 or 6 membered carbocyclic or heterocyclic ringare, for example, propylene, 1- or 2-oxopropylene, 1- or 2-oxapropylene,1-oxapropylidene, methylenedioxy, difluoromethylenedioxy, 1- or2-azapropylene, 1- or 2-azapropylidene, 1,2- or 1,3-diazapropylidene,1,3-diaza-2-oxopropylene, 1,2,3-triazapropylene, butylene, 1- or2-oxabutylene, ethylenedioxy, 1- or 2-azabutylene, or 1- or2-azabutadienylidene, or such groups carrying further substituents asdefined hereinbefore.

A 5 or 6 membered carbocyclic or heterocyclic ring formed bysubstituents R⁷ and R⁸ together with the carbon atom they are bound tois e.g. cyclopentane, cyclohexane, such rings wherein one or preferablytwo carbon atoms are replaced by oxygen, or such rings wherein onecarbon atom is replaced by oxygen and another one by nitrogen, and isoptionally further substituted by lower alkyl, lower alkoxy or loweralkoxy-lower alkyl. Preferred examples are cyclic acetals formed from acarbonyl group with ethylene glycol or monoalkylated glycerin, i.e.rings wherein the substituents R⁷ and R⁸ together represent1,2-ethylenedioxy or 3-alkoxypropylene-1,2-dioxy.

In substituted amino, the substituents are preferably those mentioned assubstituents R⁵ and R⁶. In particular, substituted amino is alkylamino,dialkylamino, optionally substituted arylamino, optionally substitutedarylalkylamino, lower alkylcarbonylamino, lower alkoxycarbonylamino oroptionally substituted aminocarbonylamino.

When X represents a group C═Y, wherein Y stands for nitrogen substitutedby hydroxy, this corresponds to an oxime function. Oximes and thecorresponding oxime alkyl ethers (nitrogen substituted by alkoxy) may bepresent in E or Z form, or as mixture of isomers. In groups wherein Ystand for nitrogen substituted by optionally substituted amino, thisgroup corresponds to an optionally substituted hydrazone function.Substituents are those considered for substituted amino above, inparticular alkylamino, dialkylamino, optionally substituted arylamino oroptionally substituted aralkylamino.

When R¹ represents OR¹² and R¹² is hydrogen, compounds of formula (I)are predominantly or exclusively present in the form of tautomers, inparticular the tautomer wherein the single bond connecting the fivemembered ring and R¹ with the meaning OH is a double bond to oxygen andthe double bond in the five membered ring between Q and the positionconnected to R¹ is a single bond and Q (with the meaning N or CR⁹) isbearing an additional hydrogen atom. When R¹ represents NR¹⁰R¹¹ and oneof R¹⁰ and R¹¹ or both R¹⁰ and R¹¹ are hydrogen, compounds of formula(I) are to some extent present in the form of tautomers, in particularthe tautomer wherein the single bond connecting the five membered ringand R¹ with the meaning NR¹⁰R¹¹ is a double bond to nitrogen and thedouble bond in the five membered ring between Q and the positionconnected to R¹ is a single bond and Q (with the meaning N or CR⁹) isbearing an additional hydrogen atom.

Salts are especially the pharmaceutically acceptable salts of compoundsof formula (I).

Such salts are formed, for example, as acid addition salts, preferablywith organic or inorganic acids, from compounds of formula (I) with abasic nitrogen atom, especially the pharmaceutically acceptable salts.Suitable inorganic acids are, for example, halogen acids, such ashydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organicacids are, for example, carboxylic, phosphonic, sulfonic or sulfamicacids, for example acetic acid, propionic acid, octanoic acid, decanoicacid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid,succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid,malic acid, tartaric acid, citric acid, amino acids, such as glutamicacid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleicacid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoicacid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylaceticacid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid,2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,1,5-naphthalene-disulfonic acid, 2-, 3- or 4-methylbenzenesulfonic acid,methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid,N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamicacid, or other organic protonic acids, such as ascorbic acid.

For isolation or purification purposes it is also possible to usepharmaceutically unacceptable salts, for example picrates orperchlorates. For therapeutic use, only pharmaceutically acceptablesalts or free compounds are employed (where applicable in the form ofpharmaceutical preparations), and these are therefore preferred.

In view of the close relationship between the novel compounds in freeform and those in the form of their salts, including those salts thatcan be used as intermediates, for example in the purification oridentification of the novel compounds, any reference to the freecompounds hereinbefore and hereinafter is to be understood as referringalso to the corresponding salts, as appropriate and expedient.

The compound of the formula (I) may be administered in the form of apro-drug which is broken down in the human or animal body to give acompound of the formula (I). Examples of pro-drugs include in vivohydrolysable esters of a compound of the formula (I).

The compounds of formula (I) have valuable pharmacological properties.The invention also relates to compounds of formula (I) as definedhereinbefore for use as medicaments.

The efficacy of the compounds of the invention in inducing apoptosis intumor cells can be demonstrated as follows:

Relative fluorescent activities of suitable tumor cell lines transfectedwith green fluorescent protein (GFP) are measured in the presence ofcompounds of the invention and of standard tumor drugs, using the methoddescribed in WO 99/35493. Suitable tumor cell lines are A20.2J, a BALB/cB cell lymphoma, PB-3c, an IL-3 dependent, non tumorigenic mastocyteline isolated from the bone marrow of a DBA/2 mouse, Jurkat, a humanacute T cell leukemia cell line, K562, a human chronic myelogenousleukemia cell line, HL60, a human acute promyelocytic leukemia cellline, Ramos and Raji, human B-cell lymphoma cell lines, H9 and Hut78,human T-cell lymphoma cell lines, HeLa and KB, human squamous cellcarcinoma cell lines, MCF7, SK-BR-3, PC3, HBL-100, SW480, H460 andH1792, human adenocarcinoma cell lines and HT-1080, a human fibrosarcomacell line. Preferred standard drugs as compounds for comparisons are: a)antimetabolites such as

-   5-fluorouracil (ICN), gemcitabine HCl (Gemzar™, Eli Lilly), b)    alkylating agents such as oxaliplatin (Eloxantin™,    Sanofi-Synthélabo), dacarbazin (Detimedac™, Medac), cyclophosphamide    (Endoxan™, Asta) and carboplatin (Paraplatin™, Bristol-Meyers    Squibb),-   c) cell-cycle inhibitor such as vinorelbine (Navelbine™, Robapharm),    vinblastine (Velbe™, Eli Lilly), docetaxel (Taxotere™, Aventis), d)    DNA breaker (top-isomerase inhibitor, intercalator, strand breaker)    such as doxorubicin HCl (Adriblastin™, Pharmacia-Upjohn), bleomycin    (Asta-Medica), irinotecan (Campto™, Aventis), etoposide phosphate    (Etopophos™, Bristol-Meyers Squibb), topotecan HCl, (Hycamtin™,    GlaxoSmithKline), e) mixtures thereof, f) compounds interfering with    the signal transduction pathway, such as caspase activity modifiers,    agonists and antagonists of cell death receptors, modifiers of    nucleases, phosphatases and kinases such as imatinib mesylate    (Gleevec™, Novartis), dexamethasone, phorbol myristate acetate,    cyclosporin A, quercetin, tamoxifen (Alexis Corporation,    Switzerland).

Apoptosis is determined in a primary screen using a fluorescence platereader and then in a secondary screen using FACS (fluorescence activatedcell scanning). Compounds causing apoptosis without substantialcytotoxic side effects are chosen for further testing andcharacterization by using a combination of the following wellestablished assays:

-   A) Nuclear staining with Hoechst 33342 dye providing information    about nuclear morphology and DNA fragmentation which are hallmarks    of apoptosis. B) MTS proliferation assay measuring the metabolic    activity of cells. Viable cells are metabolically active whereas    cells with compromised respiratory chain show a reduced activity in    this test. C) AnnexinV binding assay which reflects the    phosphatidylserine content of the outer lipid bilayer of the plasma    membrane. This event is considered an early hallmark of    apoptosis. D) Pl staining for cell cycle distribution which shows    any alterations in the distribution among the different phases of    the cell cycle. Cell cycle arresting points can be determined. E)    Proliferation assay monitoring DNA synthesis by incorporating    bromodeoxyuridine (BrdU). Inhibitory effects on growth/proliferation    can be directly determined. F) Cystein proteinase dependency,    respectively caspase dependency are determined by using specific    inhibitors. This provides information about possible involvement of    specific proteases in the mechanisms. G) Mitochondrial membrane    potential which can be detected by fluorescent cationic dyes. In    apoptotic cells the mitochondrial membrane potential dissipates    which subsequently leads to an altered fluorescence activity of the    dye.

On the basis of these studies, a compound of formula (I) according tothe invention shows therapeutic efficacy especially against neoplasticdiseases and autoimmune diseases. In particular, the compounds of theinvention are active against malignancies, e.g. epithelial neoplasms,squamous cell neoplasms, basal cell neoplasms, transitional cellpapillomas and carcinomas, adenomas und adenocarcinomas, adnexal andskin appendage neoplasms, mucoepidermoid neoplasms, cystic neoplasms,mucinous and serous neoplasms, ductal-, lobular and medullary neoplasms,acinar cell neoplasms, complex epithelial neoplasms, specialized gonadalneoplasms, paragangliomas and glomus tumors, naevi and melanomas, softtissue tumors and sarcomas, fibromatous neoplasms, myxomatous neoplasms,lipomatous neoplasms, myomatous neoplasms, complex mixed and stromalneoplasms, fibroepithelial neoplasms, synovial like neoplasms,mesothelial neoplasms, germ cell neoplasms, trophoblastic neoplasms,mesonephromas, blood vessel tumors, lymphatic vessel tumors, osseous andchondromatous neoplasms, giant cell tumors, miscellaneous bone tumors,odontogenic tumors, gliomas, neuro-epitheliomatous neoplasms,meningiomas, nerve sheath tumors, granular cell tumors and alveolar softpart sarcomas, Hodgkin's and non Hodgkin's lymphomas, otherlymphoreticular neopiasms, plasma cell tumors, mast cell tumors,immunoproliferative diseases, leukemias, miscellaneousmyeloproliferative disorders, lymphoproliferative disorders andmyelodysplastic syndromes.

The compounds of the invention are likewise active against autoimmunediseases, e.g. against systemic, discoid or subacute cutaneous lupuserythematosus, rheumatoid arthritis, antiphospholipid syndrome, CREST,progressive systemic sclerosis, mixed connective tissue disease (Sharpsyndrome), Reiter's syndrome, juvenile arthritis, cold agglutinindisease, essential mixed cryoglobulinemia, rheumatic fever, ankylosingspondylitis, chronic polyarthritis, myasthenia gravis, multiplesclerosis, chronic inflammatory demyelinating polyneuropathy,Guillan-Barré syndrome, dermatomyositis/polymyositis, autoimmunehemolytic anemia, thrompocytopenic purpura, neutropenia, type I diabetesmellitus, thyroiditis (including Hashimoto's and Grave' disease),Addison's disease, polyglandular syndrome, pemphigus (vulgaris,foliaceus, sebaceous and vegetans), bullous and cicatricial pemphigoid,pemphigoid gestationis, epidermolysis bullosa acquisita, linear IgAdisease, lichen sclerosus et atrophicus, morbus Duhring, psoriasisvulgaris, guttate, generalized pustular and localized pustularpsoriasis, vitiligo, alopecia areata, primary biliary cirrhosis,autoimmune hepatitis, all forms of glomerulonephritis, pulmonalhemorrhage (goodpasture syndrome), IgA nephropathy, pernicious anemiaand autoimmune gastritis, inflammatory bowel diseases (including colitisulcerosa and morbus Crohn), Behcet's disease, Celic-Sprue disease,autoimmune uveitis, autoimmune myocarditis, granulomatous orchitis,aspermatogenesis without orchitis, idiopatic and secondary pulmonaryfibrosis, inflammatory diseases with a possibility of autoimmunepathogensesis, such as pyoderma gangrensosum, lichen ruber, sarcoidosis(including Löfgren and cutaneous/subcutaneous type), granuloma anulare,allergic type I and type IV immunolgical reaction, asthma bronchiale,pollinosis, atopic, contact and airborne dermatitis, large vesselvasculitis (giant cell and Takayasu's arteritis), medium sized vesselvasculitis (polyarteritis nodosa, Kawasaki disease), small vesselvasculitis (Wegener's granulomatosis, Churg Strauss syndrome,microscopic polangiitis, Henoch-Schoenlein purpura, essentialcryoglobulinemic vasculitis, cutaneous leukoklastic angiitis),hypersensitivity syndromes, toxic epidermal necrolysis (Stevens-Johnsonsyndrome, erythema multiforme), diseases due to drug side effects, allforms of cutaneous, organ-specific and systemic effects due to type I-VI(Coombs classification) immunologic forms of reaction, transplantationrelated pathologies, such as acute and chronic graft versus host andhost versus graft disease, involving all organs (skin, heart, kidney,bone marrow, eye, liver, spleen, lung, muscle, central and peripheralnerve system, connective tissue, bone, blood and lymphatic vessel,genito-urinary system, ear, cartillage, primary and secondary lymphaticsystem including bone marrow, lymph node, thymus, gastrointestinaltract, including oro-pharynx, esophageus, stomach, small intestine,colon, and rectum, including parts of above mentioned organs down tosingle cell level and substructures, e.g. stem cells).

A compound of formula (I) can be administered alone or in combinationwith one or more other therapeutic agents, possible combination therapytaking the form of fixed combinations, or the administration of acompound of the invention and one or more other therapeutic agents beingstaggered or given independently of one another, or the combinedadministration of fixed combinations and one or more other therapeuticagents. A compound of formula (I) can, besides or in addition, beadministered especially for tumor therapy in combination withchemotherapy, radiotherapy, immunotherapy, surgical intervention, or acombination of these. Long-term therapy is equally possible as isadjuvant therapy in the context of other treatment strategies, asdescribed above. Other possible treatments are therapy to maintain thepatient's status after tumor regression, or even chemopreventivetherapy, for example in patients at risk. Particularly preferred is theuse of compounds of formula (I) in combination with radiotherapy.

Therapeutic agents for possible combination are especially one or morecytostatic or cytotoxic compounds, for example a chemotherapeutic agentor several selected from the group comprising indarubicin, cytarabine,interferon, hydroxyurea, bisulfan, or an inhibitor of polyaminebiosynthesis, an inhibitor of protein kinase, especially ofserine/threonine protein kinase, such as protein kinase C, or oftyrosine protein kinase, such as epidermal growth factor receptortyrosine kinase, a cytokine, a negative growth regulator, such as TGF-βor IFN-β, an aromatase inhibitor, a classical cytostatic, an inhibitorof the interaction of an SH2 domain with a phosphorylated protein, aninhibitor of Bcl-2 and modulators of the Bcl-2 family members such asBax, Bid, Bad, Bim, Nip3 and BH3-only proteins.

A compound according to the invention is not only for the (prophylacticand preferably therapeutic) management of humans, but also for thetreatment of other warm-blooded animals, for example of commerciallyuseful animals, for example rodents, such as mice, rabbits or rats, orguinea-pigs. Such a compound may also be used as a reference standard inthe test systems described above to permit a comparison with othercompounds.

With the groups of preferred compounds of formula (I) mentionedhereinafter, definitions of substituents from the general definitionsmentioned hereinbefore may reasonably be used, for example, to replacemore general definitions with more specific definitions or especiallywith definitions characterized as being preferred.

In particular, the invention refers to compounds of formula (I) wherein

-   R represents aryl or heteroaryl optionally substituted by up to four    substituents independently selected from-   alkyl, cycloalkyl, cycloalkyl-lower alkyl, halo-lower alkyl,    hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-lower    alkoxy-lower alkyl, halo-lower alkoxy-lower alkyl, acyloxy-lower    alkyl, heterocyclyl, heterocyclyl-lower alkyl, optionally    substituted phenyl, optionally substituted phenyl-lower alkyl,    optionally substituted heteroaryl, optionally substituted    heteroaryl-lower alkyl, optionally substituted alkenyl, optionally    substituted alkinyl,-   hydroxy, lower alkoxy, optionally substituted alkenyloxy, optionally    substituted alkinyloxy, cycloalkoxy, halo-lower alkoxy,    cycloalkyl-lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower    alkoxy, heterocyclyloxy, heterocyclyl-lower alkoxy, optionally    substituted phenyloxy, optionally substituted phenyl-lower alkoxy,    optionally substituted heteroaryloxy, optionally substituted    heteroaryl-lower alkoxy, sulfamoyloxy, carbamoyloxy, lower    alkylcarbonyloxy,-   amino, monoalkylamino, dialkylamino, aminocarbonylamino wherein each    of the two amino groups is optionally substituted by alkyl, alkenyl,    alkinyl or alkoxy-lower alkyl, heterocyclylcarbonylamino wherein    heterocyclyl is bound via a nitrogen atom, aminosulfonylamino    wherein each of the two amino groups is optionally substituted by    alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,    heterocyclylsulfonylamino wherein heterocyclyl is bound via a    nitrogen atom, lower alkoxycarbonylamino, lower alkylcarbonylamino    wherein alkyl is optionally substituted by one or two substituents    selected from optionally substituted phenyl, guanidyl, halogen,    cyano, alkoxy, optionally substituted phenoxy, alkylmercapto and    optionally substituted amino; lower alkenylcarbonylamino wherein    alkenyl is optionally substituted by one or two substituents    selected from lower alkyl, halo-lower alkyl, optionally substituted    phenyl, halogen, cyano, alkoxy and optionally substituted amino;    amino-lower alkyl or amino-lower alkylamino, wherein the nitrogen    atom is unsubstituted or substituted by one or two substitutents    selected from lower alkyl, cycloalkyl, cycloalkyl-lower alkyl,    hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally    substituted phenyl, optionally substituted phenyl-lower alkyl,    optionally substituted heteroaryl, optionally substituted    heteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the two    substituents on nitrogen form together with the nitrogen    heterocyclyl,-   lower alkylcarbonyl, cycloalkylcarbonyl, optionally substituted    phenylcarbonyl, optionally substituted heteroarylcarbonyl,    heterocyclylcarbonyl,-   carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower    alkoxy-lower alkoxycarbonyl, optionally substituted phenyl-lower    alkoxycarbonyl, cyano,-   lower alkylmercapto, optionally substituted phenylmercapto, lower    alkylsulfinyl, halo-lower alkylsulfinyl, optionally substituted    phenylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl,    optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, and    nitro;-   and wherein two adjacent substituents together with the atoms of    aryl or heteroaryl may form a 5 or 6 membered carbocyclic or    heterocyclic ring;-   X represents a bond; oxygen; a group C═Y, wherein Y stands for    oxygen, nitrogen substituted by hydroxy, alkoxy or optionally    substituted amino; a group —CH═CH—(C═O)_(n)— or —(C═O)_(n)—CH═CH—    wherein n is 0 or 1; or a group CR⁷R⁸;-   Q represents N or CR⁹;-   R¹ represents a group NR¹⁰R¹¹ or OR¹²;-   R² represents hydrogen, lower alkyl or amino;-   R³, R⁴, R⁵ and R⁶, independently of each other, represent hydrogen,    lower alkyl, halo-lower alkyl, cyano-lower alkyl, carboxy-lower    alkyl, cycloalkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl,    lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl,    halo-lower alkoxy-lower alkyl, heterocyclyl, heterocyclyl-lower    alkyl, optionally substituted phenyl, optionally substituted    phenyl-lower alkyl, optionally substituted heteroaryl, optionally    substituted heteroaryl-lower alkyl, optionally substituted alkenyl,    optionally substituted alkinyl,-   hydroxy, lower alkoxy, halo-lower alkoxy, cycloalkoxy,    cycloalkyl-lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower    alkoxy, heterocyclyloxy, heterocyclyl-lower alkoxy, optionally    substituted phenyloxy, optionally substituted phenyl-lower alkoxy,    optionally substituted heteroaryloxy, optionally substituted    heteroaryl-lower alkoxy, amino, carbamoyl, sulfamoyl, amino-lower    alkyl or amino-lower alkylamino, wherein in each case the nitrogen    atom is unsubstituted or substituted by one or two substitutents    selected from lower alkyl, cycloalkyl, cycloalkyl-lower alkyl,    hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally    substituted phenyl, optionally substituted phenyl-lower alkyl,    optionally substituted heteroaryl, optionally substituted    heteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the two    substituents on nitrogen form together with the nitrogen    heterocyclyl,-   lower alkylcarbonyl, cycloalkylcarbonyl, optionally substituted    phenylcarbonyl, optionally substituted heteroarylcarbonyl,    heterocyclylcarbonyl,-   carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower    alkoxy-lower alkoxycarbonyl, optionally substituted phenyl-lower    alkoxycarbonyl, cyano,-   lower alkylmercapto, optionally substituted phenylmercapto, lower    alkylsulfinyl, halo-lower alkylsulfinyl, optionally substituted    phenylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl,    optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, or    nitro,-   or R³ and R⁴, R⁴ and R⁵, or R⁵ and R⁶ together with the atoms of the    phenyl ring form a 5 or 6 membered carbocyclic or heterocyclic ring;-   R⁷ represents hydrogen, lower alkyl, cycloalkyl, cycloalkyl-lower    alkyl, lower alkenyl, lower alkinyl, optionally substituted phenyl,    lower alkoxy, lower alkenyloxy, lower alkinyloxy;-   R⁸ represents hydrogen, lower alkyl, hydroxy, lower alkoxy or lower    alkenyloxy, or-   R⁷ and R⁸ together with the carbon they are bound to form a 5 or 6    membered carbocyclic or heterocyclic ring;-   R⁹ represents hydrogen, lower alkyl or amino;-   R¹⁰ and R¹¹, independently of each other, represent hydrogen, alkyl,    cycloalkyl, cycloalkyl-alkyl, optionally substituted arylalkyl,    optionally substituted heteroarylalkyl, hydroxyalkyl, alkoxyalkyl,    hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, cyanoalkyl, carboxyalkyl,    optionally substituted alkenyl, optionally substituted alkinyl, or    lower alkylcarbonyl wherein lower alkyl is optionally substituted by    one or two substitutents selected from aryl, optionally substituted    amino, alkoxy and aryloxy;-   or R¹⁰ and R¹¹ together with the atom they are bound to form    heterocyclyl;-   R¹² is hydrogen or lower alkyl;-   tautomers and salts thereof.

More particularly, the invention refers to compounds of formula (I)wherein

-   R represents phenyl, naphthyl, thienyl, furyl, thiazolyl,    oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, pyridinyl,    pyrimidinyl, benzothienyl, benzofuryl, indolyl, benzisoxazolyl, each    optionally substituted by up to four substituents independently    selected from-   alkyl, cycloalkyl, cycloalkyl-lower alkyl, halo-lower alkyl,    hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-lower    alkoxy-lower alkyl, halo-lower alkoxy-lower alkyl, acyloxy-lower    alkyl, heterocyclyl, heterocyclyl-lower alkyl, optionally    substituted phenyl, optionally substituted phenyl-lower alkyl,    optionally substituted heteroaryl, optionally substituted    heteroaryl-lower alkyl, optionally substituted alkenyl, optionally    substituted alkinyl,-   hydroxy, lower alkoxy, optionally substituted alkenyloxy, optionally    substituted alkinyloxy, cycloalkoxy, halo-lower alkoxy,    cycloalkyl-lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower    alkoxy, heterocyclyloxy, heterocyclyl-lower alkoxy, optionally    substituted phenyloxy, optionally substituted phenyl-lower alkoxy,    optionally substituted heteroaryloxy, optionally substituted    heteroaryl-lower alkoxy, sulfamoyloxy, carbamoyloxy, lower    alkylcarbonyloxy,-   amino, monoalkylamino, dialkylamino, aminocarbonylamino wherein each    of the two amino groups is optionally substituted by alkyl, alkenyl,    alkinyl or alkoxy-lower alkyl, heterocyclylcarbonylamino wherein    heterocyclyl is bound via a nitrogen atom, aminosulfonylamino    wherein each of the two amino groups is optionally substituted by    alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,    heterocyclylsulfonylamino wherein heterocyclyl is bound via a    nitrogen atom, lower alkoxycarbonylamino, lower alkylcarbonylamino    wherein alkyl is optionally substituted by one or two substituents    selected from optionally substituted phenyl, guanidyl, halogen,    cyano, alkoxy, optionally substituted phenoxy, alkylmercapto and    optionally substituted amino; lower alkenylcarbonylamino wherein    alkenyl is optionally substituted by one or two substituents    selected from lower alkyl, halo-lower alkyl, optionally substituted    phenyl, halogen, cyano, alkoxy and optionally substituted amino;    amino-lower alkyl or amino-lower alkylamino, wherein the nitrogen    atom is unsubstituted or substituted by one or two substitutents    selected from lower alkyl, cycloalkyl, cycloalkyl-lower alkyl,    hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally    substituted phenyl, optionally substituted phenyl-lower alkyl,    optionally substituted heteroaryl, optionally substituted    heteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the two    substituents on nitrogen form together with the nitrogen    heterocyclyl,-   lower alkylcarbonyl, cycloalkylcarbonyl, optionally substituted    phenylcarbonyl, optionally substituted heteroarylcarbonyl,    heterocyclylcarbonyl,-   lower alkylsulfinyl, halo-lower alkylsulfinyl, lower alkylsulfonyl,    halo-lower alkylsulfonyl, halogen, and nitro;-   and wherein two adjacent substituents together with the atoms of    aryl or heteroaryl may form a 5 or 6 membered carbocyclic or    heterocyclic ring;-   X represents oxygen; a group C═Y, wherein Y stands for oxygen,    nitrogen substituted by hydroxy, alkoxy or optionally substituted    amino; or a group —CH═CH—(C═O)_(n)— or-   —(C═O)_(n)—CH═CH— wherein n is 0 or 1;-   Q represents N or CR⁹;-   R¹ represents a group NR¹⁰R¹¹ or OR¹²;-   R² represents hydrogen, lower alkyl or amino;-   R³, R⁴, R⁵ and R⁶, independently of each other, represent hydrogen,    lower alkyl, halo-lower alkyl, cyano-lower alkyl, carboxy-lower    alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, cycloalkoxy,    cycloalkyl-lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower    alkoxy, heterocyclyloxy, heterocyclyl-lower alkoxy, optionally    substituted phenyloxy, optionally substituted phenyl-lower alkoxy,    optionally substituted heteroaryloxy, optionally substituted    heteroaryl-lower alkoxy, amino, carbamoyl, sulfamoyl, amino-lower    alkyl or amino-lower alkylamino, wherein in each case the nitrogen    atom is unsubstituted or substituted by one or two substitutents    selected from lower alkyl, cycloalkyl, cycloalkyl-lower alkyl    hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally    substituted phenyl, optionally substituted phenyl-lower alkyl,    optionally substituted heteroaryl, optionally substituted    heteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the two    substituents on nitrogen form together with the nitrogen    heterocyclyl,-   lower alkylcarbonyl, cycloalkylcarbonyl, optionally substituted    phenylcarbonyl, optionally substituted heteroarylcarbonyl,    heterocyclylcarbonyl,-   carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower    alkoxy-lower alkoxycarbonyl, optionally substituted phenyl-lower    alkoxycarbonyl, cyano, lower alkylsulfinyl, halo-lower    alkylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl,    halogen, or nitro;-   or R³ and R⁴, R⁴ and R⁵, or R⁵ and R⁶ together represent    methylenedioxy;-   R⁹ represents hydrogen;-   R¹⁰ and R¹¹, independently of each other, represent hydrogen, alkyl,    cycloalkyl, cycloalkyl-alkyl, optionally substituted arylalkyl,    optionally substituted heteroarylalkyl, hydroxyalkyl, alkoxyalkyl,    hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, cyanoalkyl, carboxyalkyl,    optionally substituted alkenyl, optionally substituted alkinyl, or    lower alkylcarbonyl wherein lower alkyl is optionally substituted by    one or two substitutents selected from aryl, optionally substituted    amino, alkoxy and aryloxy;-   or R¹⁰ and R¹¹ together with the atom they are bound to form    heterocyclyl;-   R¹² is hydrogen;-   tautomers and pharmaceutically acceptable salts thereof.

Preferably, the invention refers to compounds of formula (I) wherein

-   R represents phenyl, naphthyl, thienyl, furyl, thiazolyl,    oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, pyridinyl,    pyrimidinyl, benzothienyl, benzofuryl, indolyl, benzisoxazolyl,    optionally substituted by up to four substituents independently    selected from-   alkyl, halo-lower alkyl, phenyl, optionally substituted heteroaryl,    lower alkoxy, optionally substituted alkenyloxy, optionally    substituted alkinyloxy, lower alkoxy-lower alkoxy,-   amino, monoalkylamino, dialkylamino, aminocarbonylamino wherein each    of the two amino groups is optionally substituted by alkyl, alkenyl,    alkinyl or alkoxy-lower alkyl, heterocyclylcarbonylamino wherein    heterocyclyl is bound via a nitrogen atom, aminosulfonylamino    wherein each of the two amino groups is optionally substituted by    alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,    heterocyclylsulfonylamino wherein heterocyclyl is bound via a    nitrogen atom, lower alkoxycarbonylamino, lower alkylcarbonylamino    wherein alkyl is optionally substituted by alkoxy or optionally    substituted amino; lower alkenylcarbonylamino wherein alkenyl is    optionally substituted by alkoxy or optionally substituted amino;    lower alkylsulfinyl, halo-lower alkylsulfinyl, lower alkylsulfonyl,    halo-lower alkylsulfonyl and halogen;-   and wherein two adjacent substituents together with the atoms of    aryl or heteroaryl may form a 5 or 6 membered carbocyclic or    heterocyclic ring;-   X represents oxygen or a group C═Y, wherein Y stands for oxygen;-   Q represents N or CR⁹;-   R¹ represents a group NR¹⁰R¹¹ or OR¹²;-   R² represents hydrogen, lower alkyl or amino;-   R³, R⁴, R⁵ and R⁶, independently of each other, represent hydrogen,    lower alkyl, halo-lower alkyl, cyano-lower alkyl, carboxy-lower    alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, cyano    or halogen;-   R⁹ represents hydrogen;-   R¹⁰ and R¹¹, independently of each other, represent hydrogen,    cyano-lower alkyl, carboxy-lower alkyl or lower alkylcarbonyl;-   R¹² is hydrogen;-   tautomers and pharmaceutically acceptable salts thereof.

More preferably, the invention refers to compounds of formula (I)wherein

-   R represents phenyl, pyridinyl or pyrimidinyl, each optionally    substituted by up to four substituents independently selected from-   alkyl, optionally substituted heteroaryl, lower alkoxy, optionally    substituted alkenyloxy, lower alkoxy-lower alkoxy,-   amino, monoalkylamino, dialkylamino, aminocarbonylamino wherein each    of the two amino groups is optionally substituted by alkyl, alkenyl,    alkinyl or alkoxy-lower alkyl, heterocyclylcarbonylamino wherein    heterocyclyl is bound via a nitrogen atom; lower alkylsulfinyl,    halo-lower alkylsulfinyl, lower alkylsulfonyl, halo-lower    alkylsulfonyl and halogen;-   and wherein two adjacent substituents together with the atoms of    aryl or heteroaryl may form a 5 or 6 membered carbocyclic or    heterocyclic ring;-   X represents oxygen or a group C═Y, wherein Y stands for oxygen;-   Q represents N or CR⁹;-   R¹ represents a group NR¹⁰R¹¹;-   R² represents hydrogen;-   R³, R⁴, R⁵ and R⁶, independently of each other, represent hydrogen,    lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, carboxy, lower    alkoxycarbonyl, cyano or halogen;-   R⁹ represents hydrogen;-   R¹⁰ represents hydrogen, hydroxy-lower alkyl, cyano-lower alkyl or    lower alkylcarbonyl;-   R¹¹ represents hydrogen;-   tautomers and pharmaceutically acceptable salts thereof.

Most preferably, the invention relates to the compounds of the Examplesand pharmaceutically acceptable salts thereof for use as a medicament,especially to the compounds of Examples 1, 2, 3, 4, 5, 6, 11, 12, 14,15, 16, 17 and 18, and to pharmaceutically acceptable salts thereof.

Especially, the invention relates to the use of a compound of formula(I), a prodrug or a pharmaceutically acceptable salt of such a compoundfor the preparation of a pharmaceutical composition for the treatment ofa neoplastic disease, autoimmune disease, transplantation relatedpathology and/or degenerative disease.

Furthermore, the invention provides a method for the treatment of aneoplastic disease, autoimmune disease, transplantation relatedpathology and/or degenerative disease, which comprises administering acompound of formula (I), a prodrug or a pharmaceutically acceptable saltthereof, wherein the radicals and symbols have the meanings as definedabove, in a quantity effective against said disease, to a warm-bloodedanimal requiring such treatment.

Method of Preparation

A compound of the invention may be prepared by processes that, thoughnot applied hitherto for the new compounds of the present invention, areknown per se, in particular

-   a process, wherein a compound of formula (II)

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are defined as for formula (I), or aderivative thereof with functional groups in protected form and/or asalt thereof, is alkylated with a halide of the formula (III)R—X—CH₂—Z(III)

-   wherein R is as defined for formula (I) and Z is a nucleophilic    leaving group;-   any protecting groups in a protected derivative of a compound of the    formula (I) are removed;-   and, if so desired, an obtainable compound of formula (I) is    converted into another compound of formula (I), a free compound of    formula (I) is converted into a salt, an obtainable salt of a    compound of formula (I) is converted into the free compound or    another salt, and/or a mixture of isomeric compounds of formula (I)    is separated into the individual isomers.

Suitable nucleophilic leaving groups Z in an alkylating agent of formula(III) are for example halides, e.g. chloride, bromide or iodide, orsulfonates, e.g. aromatic sulfonic acid esters such asbenzenesulfonates, p-toluenesulfonates or p-nitrobenzenesulfonates, oralso methanesulfonate or trifluormethanesulfonate. Also other customaryleaving groups are considered, e.g. ammonium salts, azides, diazoniumsalts, di(p-toluenesulfonyl)amines, nitrates, oxonium salts, sulfoniumsalts, or phosphonium salts.

Alkylation of a compound of formula (II) with an alkylating agent offormula (III) is performed in a manner known per se, usually in thepresence of a suitable polar or dipolar aprotic solvent, with cooling orheating, for example in a temperature range from approximately −30° C.to approximately +150° C., especially approximately around 0° C. to roomtemperature. Optionally a suitable base is added, in particularly atertiary amine base such as triethylamine or diisopropylethylamine, oran inorganic basic salt, e.g. potassium or sodium carbonate.

If one or more other functional groups, for example carboxy, hydroxy oramino, are or need to be protected in a compound of formula (II) or(III), because they should not take part in the reaction, these are suchprotecting groups as are usually applied in the synthesis of amides, inparticular peptide compounds, cephalosporins, penicillins, nucleic acidderivatives and sugars.

The protecting groups may already be present in precursors and shouldprotect the functional groups concerned against unwanted secondaryreactions, such as alkylations, acylations, etherifications,esterifications, oxidations, solvolysis, and similar reactions. It is acharacteristic of protecting groups that they lend themselves readily,i.e. without undesired secondary reactions, to removal, typically bysolvolysis, reduction, photolysis or also by enzyme activity, forexample under conditions analogous to physiological conditions, and thatthey are not present in the end products. The specialist knows, or caneasily establish, which protecting groups are suitable with thereactions mentioned hereinabove and hereinafter.

The protection of such functional groups by such protecting groups, theprotecting groups themselves, and their removal reactions are describedfor example in standard reference books for peptide synthesis and inspecial books on protective groups such as

-   J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum    Press, London and New York 1973, in “Methoden der organischen    Chemie” (Methods of organic chemistry), Houben-Weyl, 4th edition,    Volume 15/I, Georg Thieme Verlag, Stuttgart 1974, and in T. W.    Greene, “Protective Groups in Organic Synthesis”, Wiley, New York.

Other processes may be considered for the preparation of compounds offormula (I) wherein X is a bond and R is heteroaryl. For example, acompound of formula (I) wherein X is a bond and R is —C(═O)NHNH₂, i.e. ahydrazide, may be transformed by reaction with an orthoester, andamidine or an acylating agent followed by dehydratisation to give acorresponding compound wherein R is a 5-substituted 1,3,4-oxadiazol-2-ylgroup. When R is —C(NH₂)═N—OH, i.e. a hydroxamic acid amide, thecorresponding reaction leads to a group R being a 5-substituted1,2,4-oxadiazol-3-yl function. When R is —C(NH₂)═NH, i.e. an amidine,reaction with a 1,3-diketone gives a 4,6-disubstituted pyrimidin-2-ylfunction. Other heterocycles may be formed in analogous reactions.

In the additional process steps, carried out as desired, functionalgroups of the starting compounds which should not take part in thereaction may be present in unprotected form or may be protected forexample by one or more of the protecting groups mentioned hereinaboveunder “protecting groups”. The protecting groups are then wholly orpartly removed according to one of the methods described there.

In the conversion of an obtainable compound of formula (I) into anothercompound of formula (I), X with the meaning C═Y wherein Y is oxygen may,for example, be reduced to X with the meaning CR⁷R⁸ wherein R⁷ ishydrogen or hydroxy and R⁸ is hydrogen. Suitable reducing agents areknown in the art, and are, for example, metal hydrides, e.g. LiAlH₄,LiAl(OCH₃)₃H or other alkoxy-substituted lithium hydrides, NaBH₄, orBH₃, optionally in the presence of a Lewis base, e.g. AlCl₃ or BF₃, oralso with catalytical hydrogenation with hydrogen and a suitable noblemetal catalyst. Through the choice of catalyst and reaction conditions,it can be influenced whether the reaction stops at the alcohol stage (R⁷hydroxy) or to the fully saturated methylene stage (R⁷ hydrogen).

A compound of formula (I) wherein X is C═Y and Y is oxygen may bereacted with an optionally O-substituted hydroxylamine to give thecorresponding oxime or oxime ether of formula (I) wherein X is C═Y and Yis nitrogen substituted by hydroxy or alkoxy. By reaction with anoptionally substituted hydrazine, the corresponding hydrazone of formula(I) wherein X is C═Y and Y is nitrogen substituted by optionallysubstituted amino is formed.

A compound of formula (I) wherein X is C═Y and Y is oxygen may bereacted with a suitably substituted alcohol to give the correspondingacetal, i.e. a compound of formula (I) wherein X is CR⁷R⁸ and R⁷ and R⁸represent alkoxy, in the presence of an acid catalyst and optionally awater binding agent and/or a water trap. Compounds of formula (I)wherein R⁷ and R⁸ are part of a 1,3-dioxolane or a 1,3-dioxane may beobtained analogously by reaction of a compound of formula (I) wherein Xis C═O and Y is oxygen with a polyalcohol, such as glycol,propane-1,3-diol, glycerol and the like.

An obtainable compound of formula (I), wherein R¹ is amino NR¹⁰R¹¹, andR¹⁰ and/or R¹¹ is hydrogen, may be alkylated or acylated with a compoundof formula R¹⁰—Z or R¹¹—Z, respectively, wherein Z is a nucleophilicleaving group as described above, to give a compound of formula (I),wherein R¹⁰ and/or R¹¹ is different from hydrogen. Preferred acylationconditions include the use of acid anhydrides and acid chlorides atelevated temperatures, typically in a range from approximately +30° C.to approximately +150° C. An acidic or basic catalyst may be employed ifdesired. A compound of formula (I) wherein R¹⁰ and/or R¹¹ is alkyl maybe obtained by alkylation of the parent compound of formula (I). Typicalreaction conditions allowing this transformation include the combinationof a strong base, such as a metal hydride or a metal alcoholate and acompound of formula R¹⁰—Z or R¹¹-Z.

An obtainable compound of formula (I), wherein R¹ is hydroxy OR¹² andR¹² is hydrogen, may be alkylated with a compound of formula R¹²—Z,wherein Z is a nucleophilic leaving group as described above, to give acompound of formula (I), wherein R¹² is different from hydrogen. Typicalreaction conditions allowing this transformation include the combinationof a strong base, such as a metal hydride or a metal alcoholate and acompound of formula R¹²—Z.

Further amino groups present in an aryl or heteroaryl group R or in oneof the substitutents R³, R⁴, R⁵ or R⁶ may be transformed to othernitrogen containing substituents under conditions known in the art. Forexample, alkylation at nitrogen may be performed with an aldehyde underreducing conditions. For acylation the corresponding acyl chloride(Z═Cl) is preferred. Alternatively, an acid anhydride may be used, oracylation may be accomplished with the free acid (Z═OH) under conditionsused for amide formation known per se in peptide chemistry, e.g. withactivating agents for the carboxy group, such as 1-hydroxybenzotriazole,optionally in the presence of suitable catalysts or co-reagents.

Compounds of formula (I) wherein X═NOH may be alkylated allowing accessto the corresponding oxime ethers. The reaction conditions leading tothis transformation include combinations of weak bases and alkylatingagents. Typical bases include metal carbonates or bicarbonates.

Reduction of a nitro group in an nitro-substituted aryl or heteroarylgroup R or in one of the substituents R³, R⁴, R⁵ or R⁶ to give thecorresponding amino group is done, e.g., with iron powder in alcohol orwith other reducing agents.

A carboxy group in a carboxy-substituted aryl or heteroaryl group R orin one of the substituents R³, R⁴, R⁵ or R⁶ may be amidated underconditions used for amide formation known per se in peptide chemistry,e.g. with the corresponding amine and an activating agent for thecarboxy group, such as 1-hydroxybenzotriazole, optionally in thepresence of suitable catalysts or co-reagents.

A bromo or iodo substitutent in an aryl or heteroaryl group R or in oneof the substituents R³, R⁴, R⁵ or R⁶ may be replaced by phenyl or aphenyl derivative by reaction with a suitable phenylboronic acid in aSuzuki reaction, preferably in a dipolar aprotic solvent such asdimethyl formamide, or in a polar ether, e.g. tetrahydrofuran ordimethoxyethane, in the presence of a soluble palladium(0) or relatedmetal catalyst, for example tetrakis(triphenylphosphine)palladium.

Salts of a compound of formula (I) with a salt-forming group may beprepared in a manner known per se. Acid addition salts of compounds offormula (I) may thus be obtained by treatment with an acid or with asuitable anion exchange reagent.

Salts can usually be converted to free compounds, e.g. by treating withsuitable basic agents, for example with alkali metal carbonates, alkalimetal hydrogencarbonates, or alkali metal hydroxides, typicallypotassium carbonate or sodium hydroxide.

It should be emphasized that reactions analogous to the conversionsmentioned in this chapter may also take place at the level ofappropriate intermediates.

All process steps described here can be carried out under known reactionconditions, preferably under those specifically mentioned, in theabsence of or usually in the presence of solvents or diluents,preferably such as are inert to the reagents used and able to dissolvethese, in the absence or presence of catalysts, condensing agents orneutralising agents, for example ion exchangers, typically cationexchangers, for example in the H⁺ form, depending on the type ofreaction and/or reactants at reduced, normal, or elevated temperature,for example in the range from −100° C. to about 190° C., preferably fromabout −80° C. to about 150° C., for example at −80 to +60° C., at −20 to+40° C., at room temperature, or at the boiling point of the solventused, under atmospheric pressure or in a closed vessel, whereappropriate under pressure, and/or in an inert atmosphere, for exampleunder argon or nitrogen.

Salts may be present in all starting compounds and transients, if thesecontain salt-forming groups. Salts may also be present during thereaction of such compounds, provided the reaction is not therebydisturbed.

At all reaction stages, isomeric mixtures that occur can be separatedinto their individual isomers, e.g. diastereomers or enantiomers, orinto any mixtures of isomers, e.g. racemates or diastereomeric mixtures.

The invention relates also to those forms of the process in which onestarts from a compound obtainable at any stage as a transient andcarries out the missing steps, or breaks off the process at any stage,or forms a starting material under the reaction conditions, or uses saidstarting material in the form of a reactive derivative or salt, orproduces a compound obtainable by means of the process according to theinvention and further processes the said compound in situ. In thepreferred embodiment, one starts from those starting materials whichlead to the compounds described hereinabove as preferred, particularlyas especially preferred, primarily preferred, and/or preferred aboveall.

In the preferred embodiment, a compound of formula (I) is preparedaccording to or in analogy to the processes and process steps defined inthe Examples.

The compounds of formula (I), including their salts, are also obtainablein the form of hydrates, or their crystals can include for example thesolvent used for crystallization, i.e. be present as solvates.

New starting materials and/or intermediates, as well as processes forthe preparation thereof, are likewise the subject of this invention.Particularly, the invention concerns the starting material of formula(II) wherein Q represents CR⁹; R¹ represents a group NR¹⁰R¹¹; R², R³,R⁴, R⁵ and R⁶ represent hydrogen; R⁹, R¹⁰ and R¹¹ represent hydrogen;tautomers and salts thereof. In the preferred embodiment, startingmaterials are used and reaction conditions so selected as to enable thepreferred compounds to be obtained.

Starting materials of formula (II) and (III) are known, commerciallyavailable, or can be synthesized in analogy to or according to methodsthat are known in the art. In particular, a starting material of formula(II) wherein Q is N is obtained by a process, wherein ahydrazinobenzimidazole of formula (IV)

wherein R³, R⁴, R⁵ and R⁶ are defined as for formula (I), or aderivative thereof with functional groups in protected form and/or asalt thereof, is treated with a compound of formula (V)R′OCH═N—CN  (V)wherein R′ is lower alkyl, preferably ethyl.

Starting material of formula (II) wherein Q is CR⁹ is obtained in aprocess wherein the hydrazinobenzimidazole of formula (IV), wherein R³,R⁴, R⁵ and R⁶ are defined as for formula (I), or a derivative thereofwith functional groups in protected form and/or a salt thereof, istreated with a compound of formula (VI)HOCH═CR⁹—CN  (VI)wherein R⁹ is defined as for formula (I).

Starting material of formula (IV) is obtained from the correspondingmercaptobenzimidazole of formula (VII)

by oxidation and treatment with hydrazine.Pharmaceutical Preparations, Methods, and Uses

The present invention relates also to pharmaceutical compositions thatcomprise a compound of formula (I) as active ingredient and that can beused especially in the treatment of the diseases mentioned at thebeginning. Compositions for enteral administration, such as nasal,buccal, rectal or, especially, oral administration, and for parenteraladministration, such as intravenous, intramuscular or subcutaneousadministration, to warm-blooded animals, especially humans, areespecially preferred. The compositions comprise the active ingredientalone or, preferably, together with a pharmaceutically acceptablecarrier. The dosage of the active ingredient depends upon the disease tobe treated and upon the species, its age, weight, and individualcondition, the individual pharmacokinetic data, and the mode ofadministration.

The present invention relates especially to pharmaceutical compositionsthat comprise a compound of formula (I), a tautomer, a prodrug or apharmaceutically acceptable salt, or a hydrate or solvate thereof, andat least one pharmaceutically acceptable carrier.

The invention relates also to pharmaceutical compositions for use in amethod for the prophylactic or especially therapeutic management of thehuman or animal body, in particular in a method of treating neoplasticdisease, autoimmune disease, transplantation related pathology and/ordegenerative disease, especially those mentioned hereinabove.

The invention relates also to processes and to the use of compounds offormula (I) thereof for the preparation of pharmaceutical preparationswhich comprise compounds of formula (I) as active component (activeingredient).

A pharmaceutical composition for the prophylactic or especiallytherapeutic management of a neoplastic disease, autoimmune disease,transplantation related pathology and/or degenerative disease, of awarm-blooded animal, especially a human or a commercially useful mammalrequiring such treatment, comprising a novel compound of formula (I) asactive ingredient in a quantity that is prophylactically or especiallytherapeutically active against the said diseases, is likewise preferred.

The pharmaceutical compositions comprise from approximately 1% toapproximately 95% active ingredient, single-dose administration formscomprising in the preferred embodiment from approximately 20% toapproximately 90% active ingredient and forms that are not ofsingle-dose type comprising in the preferred embodiment fromapproximately 5% to approximately 20% active ingredient. Unit dose formsare, for example, coated and uncoated tablets, ampoules, vials,suppositories, or capsules. Further dosage forms are, for example,ointments, creams, pastes, foams, tinctures, lip-sticks, drops, sprays,dispersions, etc. Examples are capsules containing from about 0.05 g toabout 1.0 g active ingredient.

The pharmaceutical compositions of the present invention are prepared ina manner known per se, for example by means of conventional mixing,granulating, coating, dissolving or lyophilizing processes.

Preference is given to the use of solutions of the active ingredient,and also suspensions or dispersions, especially isotonic aqueoussolutions, dispersions or suspensions which, for example in the case oflyophilized compositions comprising the active ingredient alone ortogether with a carrier, for example mannitol, can be made up beforeuse. The pharmaceutical compositions may be sterilized and/or maycomprise excipients, for example preservatives, stabilizers, wettingagents and/or emulsifiers, solubilizers, salts for regulating osmoticpressure and/or buffers and are prepared in a manner known per se, forexample by means of conventional dissolving and lyophilizing processes.The said solutions or suspensions may comprise viscosity-increasingagents, typically sodium carboxymethylcellulose, carboxymethylcellulose,dextran, polyvinylpyrrolidone, or gelatins, or also solubilizers, e.g.Tween 80® (polyoxyethylene(20)sorbitan mono-oleate).

Suspensions in oil comprise as the oil component the vegetable,synthetic, or semi-synthetic oils customary for injection purposes. Inrespect of such, special mention may be made of liquid fatty acid estersthat contain as the acid component a long-chained fatty acid having from8 to 22, especially from 12 to 22, carbon atoms. The alcohol componentof these fatty acid esters has a maximum of 6 carbon atoms and is amonovalent or polyvalent, for example a mono-, di- or trivalent,alcohol, especially glycol and glycerol. As mixtures of fatty acidesters, vegetable oils such as cottonseed oil, almond oil, olive oil,castor oil, sesame oil, soybean oil and groundnut oil are especiallyuseful.

The manufacture of injectable preparations is usually carried out understerile conditions, as is the filling, for example, into ampoules orvials, and the sealing of the containers.

Suitable carriers are especially fillers, such as sugars, for examplelactose, saccharose, mannitol or sorbitol, cellulose preparations,and/or calcium phosphates, for example tricalcium phosphate or calciumhydrogen phosphate, and also binders, such as starches, for examplecorn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone, and/or, if desired, disintegrators, such as theabove-mentioned starches, also carboxymethyl starch, crosslinkedpolyvinylpyrrolidone, alginic acid or a salt thereof, such as sodiumalginate. Additional excipients are especially flow conditioners andlubricants, for example silicic acid, talc, stearic acid or saltsthereof, such as magnesium or calcium stearate, and/or polyethyleneglycol, or derivatives thereof.

Tablet cores can be provided with suitable, optionally enteric, coatingsthrough the use of, inter alia, concentrated sugar solutions which maycomprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycoland/or titanium dioxide, or coating solutions in suitable organicsolvents or solvent mixtures, or, for the preparation of entericcoatings, solutions of suitable cellulose preparations, such asacetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.Dyes or pigments may be added to the tablets or tablet coatings, forexample for identification purposes or to indicate different doses ofactive ingredient.

Pharmaceutical compositions for oral administration also include hardcapsules consisting of gelatin, and also soft, sealed capsulesconsisting of gelatin and a plasticizer, such as glycerol or sorbitol.The hard capsules may contain the active ingredient in the form ofgranules, for example in admixture with fillers, such as corn starch,binders, and/or glidants, such as talc or magnesium stearate, andoptionally stabilizers. In soft capsules, the active ingredient ispreferably dissolved or suspended in suitable liquid excipients, such asfatty oils, paraffin oil or liquid polyethylene glycols or fatty acidesters of ethylene or propylene glycol, to which stabilizers anddetergents, for example of the polyoxyethylene sorbitan fatty acid estertype, may also be added.

Pharmaceutical compositions suitable for rectal administration are, forexample, suppositories that consist of a combination of the activeingredient and a suppository base. Suitable suppository bases are, forexample, natural or synthetic triglycerides, paraffin hydrocarbons,polyethylene glycols or higher alkanols.

For parenteral administration, aqueous solutions of an active ingredientin water-soluble form, for example of a water-soluble salt, or aqueousinjection suspensions that contain viscosity-increasing substances, forexample sodium carboxymethylcellulose, sorbitol and/or dextran, and, ifdesired, stabilizers, are especially suitable. The active ingredient,optionally together with excipients, can also be in the form of alyophilizate and can be made into a solution before parenteraladministration by the addition of suitable solvents.

Solutions such as are used, for example, for parenteral administrationcan also be employed as infusion solutions.

Preferred preservatives are, for example, antioxidants, such as ascorbicacid, or microbicides, such as sorbic acid or benzoic acid.

The present invention relates furthermore to a method for the treatmentof a neoplastic disease, autoimmune disease, transplantation relatedpathology and/or degenerative disease, which comprises administering acompound of formula (I) or a pharmaceutically acceptable salt thereof,wherein the radicals and symbols have the meanings as defined above forformula (I), in a quantity effective against said disease, to awarm-blooded animal requiring such treatment. The compounds of formula(I) can be administered as such or especially in the form ofpharmaceutical compositions, prophylactically or therapeutically,preferably in an amount effective against the said diseases, to awarm-blooded animal, for example a human, requiring such treatment. Inthe case of an individual having a bodyweight of about 70 kg the dailydose administered is from approximately 0.05 g to approximately 5 g,preferably from approximately 0.25 g to approximately 1.5 g, of acompound of the present invention.

The present invention relates especially also to the use of a compoundof formula (I), or a pharmaceutically acceptable salt thereof,especially a compound of formula (I) which is said to be preferred, or apharmaceutically acceptable salt thereof, as such or in the form of apharmaceutical formulation with at least one pharmaceutically acceptablecarrier for the therapeutic and also prophylactic management of one ormore of the diseases mentioned hereinabove, in particular a neoplasticdisease, autoimmune disease, transplantation related pathology and/ordegenerative disease.

The preferred dose quantity, composition, and preparation ofpharmaceutical formulations (medicines) which are to be used in eachcase are described above.

The following Examples serve to illustrate the invention withoutlimiting the invention in its scope.

EXAMPLES Example 13-Amino-2-(1-[3,4-dimethylphenylcarbonylmethyl]benzimidazol-2-yl)-1,2,4-triazole

A suspension of 3-amino-2-(1H-benzimidazol-2-yl)-1,2,4-triazole (0.15 g,0.75 mol), 3,4-dimethyl phenacyl bromide (0.204 g, 0.9 mmol) and drypotassium carbonate (0.258 g, 1.87 mmol) is stirred at room temperaturefor 16 hours. The mixture is diluted with water and the productextracted with ethyl acetate. The product is purified by chromatographyon silicagel. M.p. 190-193° C., ¹H-NMR (400 MHz, d⁶-DMSO): 7.84 (m, 1H);7.77 (m, 3H); 7.65 (m, 2H); 7.50 (s, 1H); 7.33 (d, 1H); 6.22 (s, 2H);2.30 (s, 6H).

Example 1a 3-Amino-2-(1H-benzimidazol-2-yl)-1,2,4-triazole

To a solution of 2-hydrazino-1H-benzimidazole (5.0 g, 33.7 mmol) inethanol (30 ml) is added sequentially triethylamine (5 ml, 33.7 mmol)and N-cyanoformimidic acid ethyl ester (3.3 g, 33.7 mmol) with cooling.After stirring for 2 hours at 0° C. the resulting precipitate isfiltered with suction and dried to give3-amino-2-(1H-benzimidazol-2-yl)-1,2,4-triazole. ¹H-NMR (400 MHz,d⁶-DMSO): 13.0 (s, 1H); 7.77 (s, 1H); 7.70 (m, 2H); 7.50 (m, 2H); 7.20(s, 2H).

Example 1b 2-Hydrazino-1H-benzimidazole

To a mixture of 2-mercapto-1H-benzimidazole (15 g, 100 mmol), sodiumhydroxide (4.4 g, 110 mmol) and a catalytic amount of tungstic acid isadded hydrogen peroxide (43 ml, 100 mmol of a 30% aqueous solution)within 2 hours keeping the temperature at 25° C. Additional hydrogenperoxide (3×1 ml) is added to complete the transformation. After theaddition of hydrazine hydrate (15 g, 300 mmol) the mixture is heated at80° C. for 5 hours. On cooling the 2-hydrazino-1H-benzimidazole startscrystallizing. Filtration with sucking, washing with ether and dryingyields the pure product. ¹H-NMR (400 MHz, d⁶-DMSO): 10.9 (s, 1H); 7.78(m, 1H); 7.10 (m, 2H); 6.84 (m, 2H); 4.42 (s, 2H).

Example 1c N-Cyanoformimidic Acid Ethyl Ester

A mixture of cyanamide (15 g, 357 mmol) and triethyl orthoformate (110ml) is heated at reflux for 2 hours. Fractionation of the resultingmixture yields N-cyanoformimidic acid ethyl ester.

Example 2 5-Amino-2-(1-[4-methoxyphenylcarbonylmethyl]benzimidazol-2-ylpyrazole

A suspension of 5-amino-2-(1H-benzimidazol-2-yl)pyrazole (0.10 g, 0.5mmol), p-methoxyphenacyl bromide (0.204 g, 0.9 mmol) and dry potassiumcarbonate (0.173 g, 1.25 mmol) is stirred at room temperature for 16hours. The mixture is diluted with water and the product extracted withethyl acetate. The product is purified by chromatography on silicagel.M.p. 136-140° C., ¹H-NMR (400 MHz, d⁶-DMSO): 8.04 (d, 2H); 7.58 (m, 2H);7.28 (m, 3H); 7.11 (d, 2H); 6.84 (s, 2H); 6.26 (s, 2H); 5.39 (d, 1H);3.87 (s, 3H).

Example 2a 5-amino-2-(1H-benzimidazol-2-yl)pyrazole

A mixture of ethyl formate (5 ml, 62 mmol), acetonitrile (1 g, 25 mmol)and ethanol (0.5 ml) is added dropwise to a suspension of sodium hydride(0.96 g, 40 mmol) in ether at room temperature. After stirring for 16hours the volatiles are removed under reduced pressure. The residue isdiluted with water and the pH is adjusted by addition of AcOH to 7.After addition of 2-hydrazino1-H-benzimidazole (6.6 g, 45 mmol) themixture is allowed to stand for 5 hours. The pH is adjusted with sodiumhydroxide, and the mixture extracted with chloroform. The crude titleproduct is used without further purification. ¹H-NMR (400 MHz, d⁶-DMSO):12.7 (s, 1H); 7.57 (s, 1H); 7.49 (m, 2H); 7.40 (m, 2H); 7.19 (s, 2H);6.9 (s, 2H); 5.44 (d, 1H).

The following compounds were prepared in analogy to Example 1:

TABLE 1

Example No. R R¹⁰ m.p. 3

H 252-254° 4

H 236-240° 5

CH₂CH₂CN 177-180° 6

CH₂CH₂CN 179-181° 7

H 210-213° 8

H >250° 9

H 193-196° 10

H >250° 11

H 167-170° 12

H 114-117° 13

H 14

H >250° 15

H  135° 16

H 227-229°

The following compounds were prepared in analogy to Example 2:

TABLE 2

Example No. R m.p. 17

140-143° 18

166-168° 19

20

21

22

General methods for testing of compounds of the invention:

Example 23 Cell Cultures and Cell Lines

Cell lines are cultured in RPMI-1640 tissue culture medium containingeither 5% or 10% fetal calf serum, 0.05 mM 2-mercaptoethanol, 2 mMglutamine and penicillin/streptomycin 50 μg/ml (complete medium) (Sigma,Buchs, Switzerland). General growth conditions are 37° C. and 7.5% CO₂.

The following mouse cell lines (either EGFP transfected or not) arebeing used: A20.2J (ATCC: TIB-208), MC57G (ATCC: CRL-2295).

The following human cell lines (either EGFP transfected or not) arebeing used: HeLa (ATCC: CCL-2), KB (ATCC: CCL-17), MCF7 (ATCC: HTB-22),SK-BR-3 (ATCC: HTB-30), SK-Mel 1 (ATCC: HTB-67), SK-Mel 28 (ATCC:HTB-72), PC-3 (ATCC: CRL-1435), SW 480 (ATCC: CCL-228), NCI-H460 (ATCC:HTB-177), NCI-H1792 (ATCC: CRL-5895), HT1080 (ATCC: CCL-21), Jurkat(ATCC: TIB-152), Ramos (ATCC: CRL-1596), Raji (ATCC: CCL-86), H9 (ATCC:HTB-176), Hut78 (ATCC: TIB-161), K562 (ATCC: CCL 243), HL-60 (ATCC: CCL240), U-87MG (ATCC: HTB-14), HepG2 (ATCC: HB-8065), U-2 OS (ATCC:HTB-96), Saos-2 (ATCC: HTB-85), U937 (ATCC: CRL 1593), Hs 578T (ATCC:HTB 126), HBL-100 (ATCC: HTB 124), Molt-4 (ATCC: CRL 1582).

Example 24 Primary Screening Setup

All the manipulations are performed under sterile conditions. The assaysare being performed in commercially available 96 or 384 well flat bottomclear microtiter plates (Greiner, Germany) respectively, which aresuitable for tissue culture techniques. A defined number of EGFPtransfected adherent test cells (96 well plates: 10⁴-10⁵, 384 wellplates: 1500-2*10⁴) are plated out 24 hours before treatment either in75 μl (96 well plates) or 60 μl (384 well plates) complete medium perwell in order to ensure appropriate cell spreading. For this purpose aperistaltic pump (e.g. Multidrop by Thermo-Labsystems, Finland) oranother suitable device is used. Cells in suspension are plated outaccording to the same procedure but 1 h prior to treatment. Betweenseeding out and treatment or addition of compounds the cells areincubated at 37° C. under 7.5% CO₂. Subsequently, the compounds underinvestigation are added at defined concentrations (40-80 μM in either 25μl (96 well plates) or 20 μl (384 well plates) complete mediumcontaining max 4% DMSO) with an appropriate device (e.g. liquid handlingsystem, multi channel pipette etc.) resulting in a final concentrationin the test well of 10-20 μM *compound in max 1% DMSO.

Immediately after the addition of the compounds to the cells the zerofluorescence value (t=0 h) is determined by using a fluorescencemicroplate reader in order to be able to normalize the fluorescenceactivities. Afterwards, the test plates are further incubated for atotal of 48 h at 37° C. under 7.5% CO₂ and are shortly removed only forthe purpose of measurement at 8 h, 24 h and 48 h, respectively.

Example 25 Measurement and Quantification of the Primary Screening

Relative fluorescence activities of EGFP in compound treated test cellsin relation to control cells and cells treated with standard drugs aremeasured by using a BMG Fluostar microplate fluorescence reader equippedwith a filter pair for excitation/emission at 485 nm/520 nm. The optimumsignal to noise ratio is detected by using the time-resolved mode ofmeasurement with a delay of 20 us and an integration time over 1 ms. Thegain is adjusted in such a way that the control cells produce afluorescence activity of 90% of the maximum. Kinetics is performed bymeasuring the relative fluorescence activities at

t=0 h, 8 h, 24 h and 48 h. Crude fluorescence activities areindividually normalized for different cell numbers and various opticalactivities of the test compounds/plate-wells by dividing each value fromt=8 h, 24 h and 48 h by the value of t=0 h resulting in E(8), E(24) andE(48) values. Subsequently, the E(x) values are further processed byforming the inverse (Q-value) of the products E(8)*E(24)*E(48) whichresult in numbers >1 for apoptotic/necrotic activities of the compoundsand numbers <1 for proliferative activities of the compounds. Controls(untreated) show values similar to 1. Compounds producing Q values >2are being considered relevant in terms of apoptotic/necrotic activityand are subsequently tested in the secondary screening setup.

Example 26 Secondary Screening Setup

All the manipulations are performed under sterile conditions. The assaysare being performed in case of adherent cells in commercially available24 well flat bottom tissue culture plates (Greiner, Germany) and in caseof suspension cells in polypropylene tubes

(P-tubes) 1.4 ml (Matrix, UK), respectively.

Adherent test cells: 2*10⁴-4*10⁴ of EGFP transfected cells in 0.5 mlcomplete medium are plated out 24 h before treatment. At t=0 the mediumis removed and 450 μl new complete medium is added. Subsequently, 50 μlcomplete medium containing the test compound in max. 5% DMSO is addedresulting in final concentrations of 20 μM, 10 μM, 3 μM, 1 μM and 0.3 μMof the test compounds, respectively. After 48 h incubation the cells areharvested and analyzed with fluorescence activated cell scanning device(FACS Calibur™, BD Biosciences) according to standard procedures.

Suspension cells: 10⁵ test cells in 450 μl complete medium are pipettedinto P-tubes. 50 μl complete medium containing the compounds (seeadherent cells) is added immediately. After 48 h of incubation the testcells are analyzed directly on a FACSCalibur™.

Example 27 Quantification of the Secondary Screening

By monitoring the EGFP fluorescence activity in FL1 on a FACSCalibur™,it is possible to distinguish between proliferating cells, apoptoticcells and necrotic cells within the same cell population. Theproliferating cells show a high GFP fluorescence activity, the apoptoticpopulation shows an intermediate fluorescence activity whereas thenecrotic cells demonstrate a residual fluorescence activity comparableto mock-transfected cells. Within the CellQuest Software (BDBiosciences) three regions are defined in the histogram: M1 comprisingthe proliferating cells, M2 comprising the apoptotic cell population andM3 comprising the necrotic cell population. As readout the relativeabundance of the cells belonging either to M1, M2 or M3 are expressed.Compounds inducing M2 values >50% and M3 values <30% are beingconsidered relevant and are further tested and characterized in thetertiary/advanced screening setup.

Example 28 Tertiary Screening Setup

A) Hoechst 33342 Nuclear Staining

This assay is performed in 96 well tissue culture plates. Appropriatenumber of cells (adherent cells: 3-5*10³, suspension cells: 8-10*10³)are being seeded out in 80 μl complete medium. Adherent cells areincubated for 24 h for proper spreading out before addition of testcompounds while suspension cells are immediately treated with testcompounds after seeding out. The test compounds are added in 20 μlcomplete medium containing max 5% DMSO. The final compoundconcentrations in the assays are 10 μM, 3 μM, 1 μM and 0.3 μM,respectively. After 24 h or 48 h incubation at culture conditions, 10 μlmedium containing Hoechst 33342 dye (Sigma B-2261) at 2-5 μg/ml areadded to each well. The assay plates are then further incubated for 30minutes and subsequently analyzed with a standard inverted fluorescencemicroscope.

The readout allows the determination of the fraction of apoptotic nucleias well as other morphological criteria specific for apoptosis as afunction of the treatment. Results are indicated in Table 3. Thefollowing scores are used: 0 relating to no activity, 1 relating to weakactivity comprising less than 50% of the cells and score 2 relating tostrong activity comprising more than 50% of the cells.

TABLE 3 Hoechst 33342 nuclear staining Example Jurkat Jily PBLs HeLaH460 MRC5 No. Conc. 48 h 48 h 48 h 48 h 48 h 48 h 1 10 2 2 0 2 2 2 3 2 20 2 2 2 1 2 2 0 2 2 2 0.3 2 2 0 2 2 1 2 10 2 2 2 2 2 0 3 2 2 0 2 2 0 1 02 0 0 0 0 0.3 0 0 0 0 0 0 3 10 2 0 2 3 2 0 2 1 2 0 1 0.3 2 0 0 4 10 2 10 2 2 2 3 2 1 0 2 2 2 1 2 1 0 2 2 2 0.3 2 1 0 2 1 2 5 10 2 2 0 2 2 2 3 22 0 2 2 2 1 2 2 0 2 2 2 0.3 2 2 0 1 2 1 6 10 2 2 0 2 2 2 3 2 2 0 2 2 2 12 2 0 2 2 2 0.3 2 2 0 2 2 2 7 10 2 2 0 0 2 2 3 0 0 0 0 0 0 1 0 0 0 0 0 00.3 0 0 0 0 0 0 8 10 0 0 0 0 0 0 3 0 0 0 0 0 0 1 0 0 0 0 0 0 0.3 0 0 0 00 0 9 10 2 2 2 2 2 0 3 0 0 0 0 0 0 1 0 0 0 0 0 0 0.3 0 0 0 0 0 0 10 10 00 0 0 0 0 3 0 0 0 0 0 0 1 0 0 0 0 0 0 0.3 0 0 0 0 0 0 11 10 2 2 0 2 2 23 2 2 0 2 2 2 1 2 2 0 2 2 2 0.3 2 2 0 0 0 0 12 10 2 2 0 2 2 2 3 2 2 0 22 2 1 2 2 0 2 2 2 0.3 2 2 0 0 0 0 14 10 2 2 0 2 2 1 3 2 2 0 2 2 1 1 2 20 2 2 1 0.3 2 2 0 2 2 1 15 10 2 2 0 2 2 1 3 2 2 0 2 2 1 1 2 2 0 2 2 10.3 2 2 0 2 2 1 16 10 2 2 0 2 2 1 3 2 2 0 2 2 1 1 2 2 0 2 2 1 0.3 2 2 02 2 1 17 10 2 2 2 0 2 0 3 2 2 0 0 2 0 1 0 0 0 0 2 0 0.3 0 0 0 0 0 0 1810 2 2 0 2 2 1 3 2 2 0 2 2 1 1 2 2 0 2 2 1 0.3 2 2 0 2 2 1 nd: Notdetermined due to self fluorescence of the compound 0: no effect 1: Weakeffect 2: strong effectB) MTS Proliferation Assay

The assay is performed in 96 well tissue culture plates. The cells(range: 1.5*10³-10⁴) are seeded out in 80 μl complete medium 24 h priorto compound treatment. The test compounds are added in 20 μl completemedium containing max 5% DMSO. The final compound concentrations in theassays are 10 μM, 3 μM, 1 μM and 0.3 μM, respectively. The assay platesare incubated for 72 h at culture conditions. The MTS reagent isprepared according to the manufacturer's protocol (Promega G1111). 20 μlMTS reagent are added to each well, the assay plates are quickly spunand incubated for another 3 h at culture conditions. Subsequently, theplates are shortly shaked and absorption measured with amicroplate-reader at 492 nm. IC₅₀ values are determined by graphicalanalysis and are indicated in the Table 4 in μM concentration.

TABLE 4 MTS proliferation assay 1C 50 No Jurkat HeLa 1 3 3 2 3 2 2 4 3 25 3 2 6 n.a. 1 7 1 1 8 1 1 9 1 1 10 1 1 11 2 2 12 2 2 14 3 2 15 3 2 16 33 17 2 1 18 2 1 1: IC 50 > 1 μM 2: 0.1 μM < IC 50 < 1 μM 3: IC 50 < 0.1μMC) AnnexinV/7-AAD Staining

Adherent cells (1-2*10⁵) are 24 h prior to compound treatment seededinto 24 well tissue culture plates. Suspension cells are pipetted intoP-tubes immediately before treatment. Test compounds are added leadingto a final concentrations of 10 μM. After 24 h treatment cells areharvested (in case of adherent cells by trypsinization) and transferredto FACS tubes (BD Biosciences). After centrifugation and removal of thesupernatant, 100 μl complete medium containing AnnexinV-GST (10 μg) isadded, mixed and incubated at 4° C. for 30 minutes. Subsequently, thecells are washed once with medium and incubated with 100 μl anti-GSTAlexa 488 (Molecular Probes A-11131) in medium diluted 1:500 for 30minutes at 4° C. Then, cells are washed once and stained with 1 μg/ml7-aminoactinomycin D (7-AAD) (Molecular Probes A-1310) in 250 μl mediumand analyzed on the FACSCalibur™. AnnexinV is measured in FL1 whereas7-AAD is measured in FL3.

D) Pl staining for cell cycle distribution

1-2*10⁵ cells are seeded into 24 well tissue culture plates andincubated for 24 h prior to compound addition. Compounds are added for24 h in a final concentration of 3 μM or 10 μM. Adherent cells areharvested by trypsinization. The cell suspensions are fixed by adding 2parts ice cold ethanol 100% while vortexing. Then the samples are storedfor >2 h at −20° C. Subsequently the cells are washed with PBS once andresuspended in 250 μl PBS containing 50 μg/ml Pl (Calbiochem #537059),then the samples are incubated at 37° C. for 30 minutes and subsequentlyanalyzed on a FACSCalibur™ monitoring linear Pl fluorescence activity onFL2. The readout allows the detection of a possible direct or indirectinfluence of the tested compounds on the cell cycle. The followingevents can occur: a) Generation of a subG1 peak indicative for DNAfragmentation, b) increase of the cell population arrested in G2M phase.

E) BrdU Incorporation (Proliferation)

Adherent cells are seeded out at 2-4*10⁴ cells/well/ml in 24 well tissueculture plates 24 h prior to treatment. Suspension cells are seeded outat 2*10⁵ cells/ml/well in 24 well plates. Compounds are added leading tofinal concentrations of 3 μM and 10 μM, respectively. Subsequently, BrdU(Molecular Probes #B-23151) at 10 μM final concentration is added andthe plates are incubated for 48 h. After the incubation cells areprocessed according to standard procedures. The detection of theincorporated BrdU is done with the anti-bromodeoxyuridine Mab PRB-1,Alexa Fluor 660 conjugate (Molecular Probes #A-21306). The analysis isperformed on a FACSCalibur™ by monitoring the fluorescence activity onFL3. The readout reflects DNA synthesis which is a hallmark forproliferation.

F) Caspase Dependencies

Caspase dependencies are being evaluated by combining the compoundtreatment with the pan-caspase inhibitor zVAD or its control peptide zFA(ICN Pharmaceuticals #FK009 and FK029, respectively). Both peptides arebeing used at 20 μM concentration. In case of caspase dependencies aclear inhibition of the specific readout in all apoptosis tests shouldbe detected. By comparing the readout of zVAD and zFA treated sampleswith the compound control it is possible to detect caspase resp. cysteinproteinase dependencies. In case of inhibition by zVAD but not by zFA aclear caspase dependency is obvious. An inhibition by zVAD as well as byzFA points towards the involvement of cystein proteinases in theapoptotic cascade.

Example 29 Soft Capsules

5000 soft gelatin capsules, each comprising as active ingredient 0.05 gof one of the compounds of formula (I) mentioned in the precedingExamples, are prepared as follows:

250 g pulverized active ingredient is suspended in 2 liter Lauroglykol®(propylene glycol laurate, Gattefossé S.A., Saint Priest, France) andground in a wet pulverizer to produce a particle size of about 1 to 3μm. 0.419 g portions of the mixture are then introduced into softgelatin capsules using a capsule-filling machine.

1. A compound of formula (I)

wherein R represents aryl or heteroaryl optionally substituted by up tofour substituents independently selected from alkyl, cycloalkyl,cycloalkyl-lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, loweralkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, halo-loweralkoxy-lower alkyl, acyloxy-lower alkyl, heterocyclyl,heterocyclyl-lower alkyl, optionally substituted phenyl, optionallysubstituted phenyl-lower alkyl, optionally substituted heteroaryl,optionally substituted heteroaryl-lower alkyl, optionally substitutedalkenyl, optionally substituted alkinyl, hydroxy, lower alkoxy,optionally substituted alkenyloxy, optionally substituted alkinyloxy,cycloalkoxy, halo-lower alkoxy, cycloalkyl-lower alkoxy, hydroxy-loweralkoxy, lower alkoxy-lower alkoxy, heterocyclyloxy, heterocyclyl-loweralkoxy, optionally substituted phenyloxy, optionally substitutedphenyl-lower alkoxy, optionally substituted heteroaryloxy, optionallysubstituted heteroaryl-lower alkoxy, sulfamoyloxy, carbamoyloxy, loweralkylcarbonyloxy, amino, monoalkylamino, dialkylamino,aminocarbonylamino wherein each of the two amino groups is optionallysubstituted by alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,heterocyclylcarbonylamino wherein heterocyclyl is bound via a nitrogenatom, aminosulfonylamino wherein each of the two amino groups isoptionally substituted by alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,heterocyclylsulfonylamino wherein heterocyclyl is bound via a nitrogenatom, lower alkoxycarbonylamino, lower alkylcarbonylamino wherein alkylis optionally substituted by one or two substituents selected fromoptionally substituted phenyl, guanidyl, halogen, cyano, alkoxy,optionally substituted phenoxy, alkylmercapto and optionally substitutedamino; lower alkenylcarbonylamino wherein alkenyl is optionallysubstituted by one or two substituents selected from lower alkyl,halo-lower alkyl, optionally substituted phenyl, halogen, cyano, alkoxyand optionally substituted amino; amino-lower alkyl or amino-loweralkylamino, wherein the nitrogen atom is unsubstituted or substituted byone or two substitutents selected from lower alkyl, cycloalkyl,cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,optionally substituted phenyl, optionally substituted phenyl-loweralkyl, optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the twosubstituents on nitrogen form together with the nitrogen heterocyclyl,lower alkylcarbonyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl, carboxy, lower alkoxycarbonyl, hydroxy-loweralkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, optionallysubstituted phenyl-lower alkoxycarbonyl, cyano, lower alkylmercapto,optionally substituted phenylmercapto, lower alkylsulfinyl, halo-loweralkylsulfinyl, optionally substituted phenylsulfinyl, loweralkylsulfonyl, halo-lower alkylsulfonyl, optionally substitutedphenylsulfonyl, aralkylsulfonyl, halogen, and nitro; and wherein twoadjacent substituents together with the atoms of aryl or heteroaryl mayform a 5 or 6 membered carbocyclic or heterocyclic ring; X represents abond; oxygen; a group C═Y, wherein Y stands for oxygen, nitrogensubstituted by hydroxy, alkoxy or optionally substituted amino; a group—CH═CH—(C═O)_(n)— or —(C═O)_(n)—CH═CH— wherein n is 0 or 1; or a groupCR⁷R⁸; Q represents CR⁹; R¹ represents a group NR¹⁰R¹¹ or OR¹²; R²represents hydrogen, lower alkyl or amino; R³, R⁴, R⁵ and R⁶,independently of each other, represent hydrogen, lower alkyl, halo-loweralkyl, cyano-lower alkyl, carboxy-lower alkyl, cycloalkyl,cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,lower alkoxy-lower alkoxy-lower alkyl, halo-lower alkoxy-lower alkyl,heterocyclyl, heterocyclyl-lower alkyl, optionally substituted phenyl,optionally substituted phenyl-lower alkyl, optionally substitutedheteroaryl, optionally substituted heteroaryl-lower alkyl, optionallysubstituted alkenyl, optionally substituted alkinyl, hydroxy, loweralkoxy, halo-lower alkoxy, cycloalkoxy, cycloalkyl-lower alkoxy,hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, heterocyclyloxy,heterocyclyl-lower alkoxy, optionally substituted phenyloxy, optionallysubstituted phenyl-lower alkoxy, optionally substituted heteroaryloxy,optionally substituted heteroaryl-lower alkoxy, amino, carbamoyl,sulfamoyl, amino-lower alkyl or amino-lower alkylamino, wherein in eachcase the nitrogen atom is unsubstituted or substituted by one or twosubstitutents selected from lower alkyl, cycloalkyl, cycloalkyl-loweralkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionallysubstituted phenyl, optionally substituted phenyl-lower alkyl,optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the twosubstituents on nitrogen form together with the nitrogen heterocyclyl,lower alkylcarbonyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl, carboxy, lower alkoxycarbonyl, hydroxy-loweralkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, optionallysubstituted phenyl-lower alkoxycarbonyl, cyano, lower alkylmercapto,optionally substituted phenylmercapto, lower alkylsulfinyl, halo-loweralkylsulfinyl, optionally substituted phenylsulfinyl, loweralkylsulfonyl, halo-lower alkylsulfonyl, optionally substitutedphenylsulfonyl, aralkylsulfonyl, halogen, or nitro, or R³ and R⁴, R⁴ andR⁵, or R⁵ and R⁶ together with the atoms of the phenyl ring form a 5 or6 membered carbocyclic or heterocyclic ring; R⁷ represents hydrogen,lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, lower alkenyl, loweralkinyl, optionally substituted phenyl, lower alkoxy, lower alkenyloxy,or lower alkinyloxy; R⁸ represents hydrogen, lower alkyl, hydroxy, loweralkoxy or lower alkenyloxy, or R⁷ and R⁸ together with the carbon theyare bound to form a 5 or 6 membered carbocyclic or heterocyclic ring; R⁹represents hydrogen, lower alkyl or amino; R¹⁰ and R¹¹ independently ofeach other, represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl,alkoxyalkoxyalkyl, cyanoalkyl, carboxyalkyl, optionally substitutedalkenyl, optionally substituted alkinyl, or lower alkylcarbonyl whereinlower alkyl is optionally substituted by one or two substitutentsselected from aryl, optionally substituted amino, alkoxy and aryloxy; orR¹⁰ and R¹¹ together with the atom they are bound to form heterocyclyl;R¹² is hydrogen, lower alkyl, acyl or aminocarbonyl wherein amino isunsubstituted or substituted by lower alkyl; or tautomers or saltsthereof.
 2. The compound of formula (I) according to claim 1 wherein Rrepresents aryl or heteroaryl optionally substituted by up to foursubstituents independently selected from alkyl, cycloalkyl,cycloalkyl-lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, loweralkoxy-lower alkyl, acyloxy-lower alkyl, heterocyclyl,heterocyclyl-lower alkyl, optionally substituted phenyl, optionallysubstituted phenyl-lower alkyl, optionally substituted heteroaryl,optionally substituted heteroaryl-lower alkyl, optionally substitutedalkenyl, optionally substituted alkinyl, hydroxy, lower alkoxy,hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, optionally substitutedphenyloxy, optionally substituted heteroaryloxy, sulfamoyloxy,carbamoyloxy, lower alkylcarbonyloxy, amino, monoalkylamino,dialkylamino, aminocarbonylamino wherein each of the two amino groups isoptionally substituted by alkyl, alkenyl, alkinyl,heterocyclyl-carbonylamino wherein heterocyclyl is bound via a nitrogenatom, lower alkoxycarbonylamino, lower alkylcarbonylamino wherein alkylis optionally substituted by one or two substituents selected fromoptionally substituted phenyl, halogen, cyano, alkoxy, optionallysubstituted phenoxy, alkylmercapto and optionally substituted amino;lower alkenylcarbonylamino wherein alkenyl is optionally substituted byone or two substituents selected from lower alkyl, halo-lower alkyl,optionally substituted phenyl, halogen, cyano, alkoxy and optionallysubstituted amino; amino-lower alkyl wherein the nitrogen atom isunsubstituted or substituted by one or two substitutents selected fromlower alkyl, cycloalkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl,lower alkoxy-lower alkyl, optionally substituted phenyl, optionallysubstituted heteroaryl and optionally substituted heteroaryl loweralkylcarbonyl, or wherein the two substituents on nitrogen form togetherwith the nitrogen heterocyclyl, lower alkylcarbonyl, cycloalkylcarbonyl,optionally substituted phenylcarbonyl, optionally substitutedheteroarylcarbonyl, heterocyclylcarbonyl, carboxy, lower alkoxycarbonyl,cyano, lower alkylmercapto, optionally substituted phenylmercapto, loweralkylsulfinyl, optionally substituted phenylsulfinyl, loweralkylsulfonyl, optionally substituted phenylsulfonyl, aralkylsulfonyl,halogen, and nitro; and wherein two adjacent substituents together withthe atoms of aryl or heteroaryl may form a 5 or 6 membered carbocyclicor heterocyclic ring; X represents a bond; oxygen; a group C═Y, whereinY stands for oxygen, nitrogen substituted by hydroxy or alkoxy; a group—CH═CH—(C═O )_(n)— or —(C═O) _(n)—CH═CH—wherein n is 0 or 1; or a groupCR⁷R⁸; Q represents CR⁹; R¹ represents a group NR¹⁰R¹¹ or OR¹²; R²represents hydrogen, lower alkyl or amino; R³, R⁴, R⁵ and R⁶,independently of each other, represent hydrogen, lower alkyl, halo-loweralkyl, cyano-lower alkyl, carboxy-lower alkyl, cycloalkyl,cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,heterocyclyl, heterocyclyl-lower alkyl, optionally substituted phenyl,optionally substituted phenyl-lower alkyl, optionally substitutedheteroaryl, optionally substituted heteroaryl-lower alkyl, optionallysubstituted alkenyl, optionally substituted alkinyl, hydroxy, loweralkoxy, cycloalkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy,heterocyclyloxy, heterocyclyl-lower alkoxy, optionally substitutedphenyloxy, optionally substituted heteroaryloxy, amino, carbamoyl,sulfamoyl, amino-lower alkyl, wherein in each case the nitrogen atom isunsubstituted or substituted by one or two substitutents selected fromlower alkyl, cycloalkyl, cycloalkyl-lower alkyl, optionally substitutedheteroaryl lower alkylcarbonyl, or wherein the two substituents onnitrogen form together with the nitrogen heterocyclyl, loweralkylcarbonyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl, carboxy, lower alkoxycarbonyl, optionallysubstituted phenyl-lower alkoxycarbonyl, cyano, lower alkylmercapto,lower alkylsulfinyl, halo-lower alkylsulfinyl, optionally substitutedphenylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl,optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, ornitro, or R³ and R⁴, R⁴ and R⁵, or R⁵ and R⁶ together with the atoms ofthe phenyl ring form a 5 or 6 membered carbocyclic or heterocyclic ring;R⁷ represents hydrogen, lower alkyl, cycloalkyl, cycloalkyl-lower alkyl,lower alkenyl, lower alkinyl, optionally substituted phenyl, loweralkoxy, lower alkenyloxy, or lower alkinyloxy; R⁸ represents hydrogen,lower alkyl, hydroxy, lower alkoxy or lower alkenyloxy, R⁹ representshydrogen, lower alkyl or amino; R¹⁰ and R¹¹, independently of eachother, represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl,alkoxyalkoxyalkyl, cyanoalkyl, carboxyalkyl, optionally substitutedalkenyl, optionally substituted alkinyl, or lower alkylcarbonyl whereinlower alkyl is optionally substituted by one or two substitutentsselected from aryl, optionally substituted amino, alkoxy and aryloxy; orR¹⁰ and R¹¹ together with the atom they are bound to form heterocyclyl;R¹² is hydrogen, lower alkyl, acyl or aminocarbonyl wherein amino isunsubstituted or substituted by lower alkyl; or tautomers or saltsthereof.
 3. The compound of formula (I) according to claim 1 wherein Rrepresents aryl or heteroaryl optionally substituted by up to foursubstituents independently selected from alkyl, cycloalkyl,cycloalkyl-lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, loweralkoxy-lower alkyl, acyloxy-lower alkyl, heterocyclyl,heterocyclyl-lower alkyl, optionally substituted phenyl, optionallysubstituted phenyl-lower alkyl, optionally substituted heteroaryl,optionally substituted heteroaryl-lower alkyl, optionally substitutedalkenyl, optionally substituted alkinyl, hydroxy, lower alkoxy,hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, optionally substitutedphenyloxy, optionally substituted heteroaryloxy, sulfamoyloxy,carbamoyloxy, lower alkylcarbonyloxy, amino, monoalkylamino,dialkylamino, aminocarbonylamino wherein each of the two amino groups isoptionally substituted by alkyl, alkenyl, alkinyl,heterocyclyl-carbonylamino wherein heterocyclyl is bound via a nitrogenatom, lower alkoxycarbonylamino, lower alkylcarbonylamino wherein alkylis optionally substituted by one or two substituents selected fromoptionally substituted phenyl, halogen, cyano, alkoxy, optionallysubstituted phenoxy, alkylmercapto and optionally substituted amino;lower alkenylcarbonylamino wherein alkenyl is optionally substituted byone or two substituents selected from lower alkyl, halo-lower alkyl,optionally substituted phenyl, halogen, cyano, alkoxy and optionallysubstituted amino; amino-lower alkyl wherein the nitrogen atom isunsubstituted or substituted by one or two substitutents selected fromlower alkyl, cycloalkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl,lower alkoxy-lower alkyl, optionally substituted phenyl, optionallysubstituted heteroaryl and optionally substituted heteroaryl loweralkylcarbonyl, or wherein the two substituents on nitrogen form togetherwith the nitrogen heterocyclyl, lower alkylcarbonyl, cycloalkylcarbonyl,optionally substituted phenylcarbonyl, optionally substitutedheteroarylcarbonyl, heterocyclylcarbonyl, carboxy, lower alkoxycarbonyl,cyano, lower alkylmercapto, optionally substituted phenylmercapto, loweralkylsulfinyl, optionally substituted phenylsulfinyl, loweralkylsulfonyl, optionally substituted phenylsulfonyl, aralkylsulfonyl,halogen, and nitro; and wherein two adjacent substituents together withthe atoms of aryl or heteroaryl may form a 5 or 6 membered carbocyclicor heterocyclic ring; X represents a bond; oxygen; a group C═Y, whereinY stands for oxygen, nitrogen substituted by hydroxy, alkoxy; a group—CH═CH—(C═O)_(n)— or —(C═O)_(n)—CH═CH—wherein n is 0 or 1; or a groupCR⁷R⁸; Q represents CR⁹; R¹ represents a group NR¹⁰R¹¹ or OR¹²; R²represents hydrogen, lower alkyl or amino; R³, R⁴, R⁵ and R⁶,independently of each other, represent hydrogen, lower alkyl, halo-loweralkyl, cyano-lower alkyl, carboxy-lower alkyl, cycloalkyl,cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,heterocyclyl, heterocyclyl-lower alkyl, optionally substituted phenyl,optionally substituted phenyl-lower alkyl, optionally substitutedheteroaryl, optionally substituted heteroaryl-lower alkyl, optionallysubstituted alkenyl, optionally substituted alkinyl, hydroxy, loweralkoxy, cycloalkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy,heterocyclyloxy, heterocyclyl-lower alkoxy, optionally substitutedphenyloxy, optionally substituted heteroaryloxy, amino, carbamoyl,sulfamoyl, amino-lower alkyl, wherein in each case the nitrogen atom isunsubstituted or substituted by one or two substitutents selected fromlower alkyl, cycloalkyl, cycloalkyl-lower alkyl, optionally substitutedheteroaryl lower alkylcarbonyl, or wherein the two substituents onnitrogen form together with the nitrogen heterocyclyl, loweralkylcarbonyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl, carboxy, lower alkoxycarbonyl, optionallysubstituted phenyl-lower alkoxycarbonyl, cyano, lower alkylmercapto,lower alkylsulfinyl, halo-lower alkylsulfinyl, optionally substitutedphenylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl,optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, ornitro, or R³ and R4, R4 and R⁵, or R⁵ and R⁶ together with the atoms ofthe phenyl ring form a 5 or 6 membered carbocyclic or heterocyclic ring;R⁷ represents hydrogen, lower alkyl, cycloalkyl, cycloalkyl-lower alkyl,lower alkenyl, lower alkinyl, optionally substituted phenyl, loweralkoxy, lower alkenyloxy, or lower alkinyloxy; R⁸ represents hydrogen,lower alkyl, hydroxy, lower alkoxy or lower alkenyloxy, R⁹ representshydrogen, lower alkyl or amino; R¹⁰ and R¹¹, independently of eachother, represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl,alkoxyalkoxyalkyl, cyanoalkyl, carboxyalkyl, optionally substitutedalkenyl, optionally substituted alkinyl, or lower alkylcarbonyl whereinlower alkyl is optionally substituted by one or two substitutentsselected from aryl, optionally substituted amino, alkoxy and aryloxy; orR¹⁰ and R¹¹ together with the atom they are bound to form heterocyclyl;R¹² is hydrogen or lower alkyl; or tautomers or salts thereof.
 4. Thecompound of formula (I) according to claim 1 wherein R representsphenyl, naphthyl, thienyl, furyl, thiazolyl, oxadiazolyl, thiadiazolyl,imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, benzothienyl, benzofuryl,indolyl or benzisoxazolyl, optionally substituted by up to foursubstituents independently selected from alkyl, halo-lower alkyl,phenyl, optionally substituted heteroaryl, hydroxy, lower alkoxy, loweralkoxy-lower alkoxy, amino, monoalkylamino, dialkylamino,aminocarbonylamino wherein each of the two amino groups is optionallysubstituted by alkyl, alkenyl, alkinyl, heterocyclyl-carbonylaminowherein heterocyclyl is bound via a nitrogen atom, loweralkoxycarbonylamino, lower alkylcarbonylamino wherein alkyl isoptionally substituted by alkoxy or optionally substituted amino; loweralkenylcarbonylamino wherein alkenyl is optionally substituted by alkoxyor optionally substituted amino; lower alkylsulfinyl, loweralkylsulfonyl, lower alkylcarbonyl, carboxy, lower alkoxycarbonyl, cyanoor halogen; or wherein two adjacent substituents together with the atomsof aryl or heteroaryl may form a 5 or 6 membered carbocyclic orheterocyclic ring; X represents oxygen or a group C═Y, wherein Y standsfor oxygen; Q represents CR⁹; R¹ represents a group NR¹⁰R¹¹ or OR¹²; R²represents hydrogen, lower alkyl or amino; R³, R⁴, R⁵ and R⁶,independently of each other, represent hydrogen, lower alkyl, halo-loweralkyl, cyano-lower alkyl, carboxy-lower alkyl, hydroxy, lower alkoxy,carboxy, lower alkoxycarbonyl, cyano or halogen; R⁹ represents hydrogen;R¹⁰ and R¹¹, independently of each other, represent hydrogen,cyano-lower alkyl, carboxy-lower alkyl or lower alkylcarbonyl; R¹² ishydrogen; or tautomers or pharmaceutically acceptable salts thereof. 5.The compound of formula (I) according to claim 1 wherein R representsphenyl, pyridinyl or pyrimidinyl, each optionally substituted by up tofour substituents independently selected from alkyl, optionallysubstituted heteroaryl, lower alkoxy, lower alkoxy-lower alkoxy, amino,monoalkylamino, dialkylamino, aminocarbonylamino wherein each of the twoamino groups is optionally substituted by alkyl, alkenyl, alkinyl,heterocyclylcarbonylamino wherein heterocyclyl is bound via a nitrogenatom; lower alkylsulfinyl, lower alkylsulfonyl, lower alkylcarbonyl,carboxy, lower alkoxycarbonyl, cyano and halogen; and wherein twoadjacent substituents together with the atoms of aryl or heteroaryl mayform a 5 or 6 membered carbocyclic or heterocyclic ring; X representsoxygen or a group C═Y, wherein Y stands for oxygen; Q represents CR⁹; R¹represents a group NR¹⁰R¹¹; R² represents hydrogen; R³, R⁴, R⁵ and R⁶,independently of each other, represent hydrogen, lower alkyl, halo-loweralkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, cyano orhalogen; R⁹ represents hydrogen; R¹⁰ represents hydrogen, hydroxy-loweralkyl, cyano-lower alkyl or lower alkylcarbonyl; R¹¹ representshydrogen; or tautomers or pharmaceutically acceptable salts thereof. 6.The compound of formula (I) according to claim 1 wherein R representsaryl or heteroaryl, in particular phenyl, naphthyl, thienyl, furyl,thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, pyridinyl,pyrimidinyl, benzothienyl, benzofuryl, indolyl, benzisoxazolyl,optionally substituted by up to four substituents independently selectedfrom alkyl, halo-lower alkyl, hydroxy, lower alkoxy, amino,monoalkylamino, dialkylamino, lower alkylcarbonylamino loweralkylcarbonyl, carboxy, lower alkoxycarbonyl, cyano or halogen, Xrepresents a group C═Y, wherein Y stands for oxygen, Q represents CR⁹;R¹ represents a group NR¹⁰R¹¹; R² represents hydrogen, lower alkyl oramino; R³, R⁴, R⁵ and R⁶ represent hydrogen; R⁹ represents hydrogen; R¹⁰and R¹¹, independently of each other, represent hydrogen, alkyl,hydroxyalkyl, alkoxyalkyl, cyanoalkyl, carboxyalkyl; or tautomers orsalts thereof.
 7. A compound of formula (I) according to claim 1 whereinR represents 3,4-dimethylphenyl, 4-methoxyphenyl or 4-chlorophenyl; Xrepresents a group C═Y, wherein Y stands for oxygen; Q represents CR⁹;R¹ represents a group NR¹⁰R¹¹; R², R³, R⁴, R⁵, R⁶, R⁹, R¹⁰ and R¹¹represent hydrogen; or tautomers or pharmaceutically acceptable saltsthereof.
 8. A compound of formula (II)

wherein Q represents CR⁹; R¹ represents a group NR¹⁰R¹¹; R², R³, R⁴, R⁵and R⁶ represent hydrogen; R⁹, R¹⁰ and R¹¹ represent hydrogen; tautomersor salts thereof.
 9. A compound of the formula:

wherein R represents aryl or heteroaryl optionally substituted by up tofour substituents independently selected from alkyl, cycloalkyl,cycloalkyl-lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, loweralkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, halo-loweralkoxy-lower alkyl, acyloxy-lower alkyl, heterocyclyl,heterocyclyl-lower alkyl, optionally substituted phenyl, optionallysubstituted phenyl-lower alkyl, optionally substituted heteroaryl,optionally substituted heteroaryl-lower alkyl, optionally substitutedalkenyl, optionally substituted alkinyl, hydroxy, lower alkoxy,optionally substituted alkenyloxy, optionally substituted alkinyloxy,cycloalkoxy, halo-lower alkoxy, cycloalkyl-lower alkoxy, hydroxy-loweralkoxy, lower alkoxy-lower alkoxy, heterocyclyloxy, heterocyclyl-loweralkoxy, optionally substituted phenyloxy, optionally substitutedphenyl-lower alkoxy, optionally substituted heteroaryloxy, optionallysubstituted heteroaryl-lower alkoxy, sulfamoyloxy, carbamoyloxy, loweralkylcarbonyloxy, amino, monoalkylamino, dialkylamino,aminocarbonylamino wherein each of the two amino groups is optionallysubstituted by alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,heterocyclylcarbonylamino wherein heterocyclyl is bound via a nitrogenatom, aminosulfonylamino wherein each of the two amino groups isoptionally substituted by alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,heterocyclylsulfonylamino wherein heterocyclyl is bound via a nitrogenatom, lower alkoxycarbonylamino, lower alkylcarbonylamino wherein alkylis optionally substituted by one or two substituents selected fromoptionally substituted phenyl, guanidyl, halogen, cyano, alkoxy,optionally substituted phenoxy, alkylmercapto and optionally substitutedamino; lower alkenylcarbonylamino wherein alkenyl is optionallysubstituted by one or two substituents selected from lower alkyl,halo-lower alkyl, optionally substituted phenyl, halogen, cyano, alkoxyand optionally substituted amino; amino-lower alkyl or amino-loweralkylamino, wherein the nitrogen atom is unsubstituted or substituted byone or two substitutents selected from lower alkyl, cycloalkyl,cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,optionally substituted phenyl, optionally substituted phenyl-loweralkyl, optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the twosubstituents on nitrogen form together with the nitrogen heterocyclyl,lower alkylcarbonyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl, carboxy, lower alkoxycarbonyl, hydroxy-loweralkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, optionallysubstituted phenyl-lower alkoxycarbonyl, cyano, lower alkylmercapto,optionally substituted phenylmercapto, lower alkylsulfinyl, halo-loweralkylsulfinyl, optionally substituted phenylsulfinyl, loweralkylsulfonyl, halo-lower alkylsulfonyl, optionally substitutedphenylsulfonyl, aralkylsulfonyl, halogen, and nitro; and wherein twoadjacent substituents together with the atoms of aryl or heteroaryl mayform a 5 or 6 membered carbocyclic or heterocyclic ring; or tautomers orpharmaceutically acceptable salts thereof.
 10. The compound of claim 9wherein R is phenyl or substituted phenyl.
 11. The compound of claim 10wherein R is phenyl substituted with halogen, lower alkyl, amino, monolower alkyl amino, di-lower alkyl amino, lower alkoxy or halogen. 12.The compound of claim 11 wherein said phenyl is lower alkyl substituted.13. The compound of claim 12 wherein said compound is5-amino-1-(1-[3,4-dimethylphenylcarbonylmethyl]benzimidazol-2-yl)-pyrazoleor tautomers or pharmaceutically acceptable salts thereof.
 14. Thecompound of claim 11 wherein said phenyl is substituted with halogen.15. The compound of claim 14 wherein said compound is5-amino-1-(1-[4-chlorophenylcarbonylmethyl]benzimidazol-2-yl)-pyrazoleor tautomers or pharmaceutically acceptable salts thereof.
 16. Thecompound of claim 11 wherein said phenyl is substituted with loweralkoxy.
 17. The compound of claim 16 wherein said compound is5-amino-1-(1-[4-methoxyphenylcarbonylmethyl]benzimidazol-2-yl)-pyrazoleor tautomers or pharmaceutically acceptable salts thereof.
 18. Thecompound claim 9 wherein R is pyridyl or substituted pyridyl.
 19. Thecompound of claim 18 wherein the pyridyl is substituted with halogen,lower alkyl, amino, mono lower alkyl amino, di-lower alkyl amino, loweralkoxy or halogen.
 20. The compound of claim 19 wherein said pyridyl issubstituted with amino, or a mono or di-lower alkyl amino.
 21. Thecompound of claim 19 wherein said compound is5-amino-1-(1-[1-amino-5-pyridylcarbonylmethyl]benzimidazol-2-yl)-pyrazole or tautomers or pharmaceutically acceptable salts thereof. 22.The compound of claim 19 wherein said compound is5-amino-1-(1-[2-dimethylamino-5-pyridylcarbonylmethyl]benzimidazol-2-yl)-pyrazoleor tautomers or pharmaceutically acceptable salts thereof.
 23. Thecompound of claim 19 wherein said pyridyl is substituted with loweralkoxy.
 24. The compound of claim 23 wherein said compound is5-amino-1-(1-[2-methoxy-5-pyridylcarbonylmethyl]benzimidazol-2-yl)-pyrazoleor tautomers or pharmaceutically acceptable salts thereof.
 25. Thecompound of claim 19 wherein said compound is5-amino-1-(1-[2-chloro-5-pyridylcarbonylmethyl]benzimidazol-2-yl)-pyrazoleor tautomers or pharmaceutically acceptable salts thereof.